Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication)

<!DOCTYPE html> <html lang="en" > <head > <meta charset="UTF-8" /> <meta http-equiv="X-UA-Compatible" content="IE=edge" /> <meta name="HandheldFriendly" content="True" /> <meta name="MobileOptimized" content="320" /> <meta name="viewport" content="width=device-width, initial-scale=1.0" /> <link rel="stylesheet" href="/static/assets/style-70b9163a.css" /> <script type="module" crossorigin="" src="/static/assets/base_style-ec2bc71e.js"></script> <link rel="stylesheet" href="/static/assets/style-ef962842.css" /> <link rel="stylesheet" href="/static/assets/style-3ade8b5c.css" /> <script type="module" crossorigin="" src="/static/assets/article_style-d757a0dd.js"></script> <style> @media screen and (min-width: 64em) { div.pmc-wm { background: repeat-y; background-image: url("data:image/svg+xml,%3Csvg xmlns='http://www.w3.org/2000/svg' width='20' height='350' xmlns:xlink='http://www.w3.org/1999/xlink'%3E%3Cdefs%3E%3Cfilter x='-.02' y='0' width='1.05' height='1' id='c'%3E%3CfeFlood flood-color='%23FFF'/%3E%3CfeComposite in='SourceGraphic'/%3E%3C/filter%3E%3Ctext id='b' font-family='Helvetica' font-size='11pt' style='opacity:1;fill:%23005ea2;stroke:none;text-anchor:middle' x='175' y='14'%3EAuthor Manuscript%3C/text%3E%3Cpath id='a' style='fill:%23005ea2' d='M0 8h350v3H0z'/%3E%3C/defs%3E%3Cuse xlink:href='%23a' transform='rotate(90 10 10)'/%3E%3Cuse xlink:href='%23b' transform='rotate(90 10 10)' filter='url(%23c)'/%3E%3C/svg%3E"); padding-left: 3rem; } } </style> <link rel="apple-touch-icon" sizes="180x180" href="/static/img/favicons/apple-touch-icon.png" /> <link rel="icon" type="image/png" sizes="48x48" href="/static/img/favicons/favicon-48x48.png" /> <link rel="icon" type="image/png" sizes="32x32" href="/static/img/favicons/favicon-32x32.png" /> <link rel="icon" type="image/png" sizes="16x16" href="/static/img/favicons/favicon-16x16.png" /> <link rel="manifest" href="/static/img/favicons/site.webmanifest" /> <link rel="mask-icon" href="/static/img/favicons/safari-pinned-tab.svg" color="#0071bc" /> <meta name="msapplication-config" content="/static/img/favicons/browserconfig.xml" /> <meta name="theme-color" content="#ffffff" /> <title> Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication) - PMC </title>  <meta name="ncbi_app" content="cloudpmc-viewer" /> <meta name="ncbi_db" content="pmc" /> <meta name="ncbi_phid" content="E5FDE6C3746A5E9305E6C30036E2E952.m_1" />  <meta name="ncbi_pdid" content="article" /> <link rel="preconnect" href="https://www.google-analytics.com" /> <link rel="dns-prefetch" href="https://cdn.ncbi.nlm.nih.gov" /> <link rel="preconnect" href="https://code.jquery.com" /> <meta name="ncbi_domain" content="nihpa"> <meta name="ncbi_type" content="fulltext"> <meta name="ncbi_pcid" content="manuscript"> <link rel="canonical" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/"> <meta name="robots" content="INDEX,NOFOLLOW,NOARCHIVE"> <meta name="citation_journal_title" content="Microbiology & infectious diseases (Wilmington, Del.)"> <meta name="citation_title" content="Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication)"> <meta name="citation_author" content="Brett L Hurst"> <meta name="citation_author_institution" content="Institute of Antiviral Research, Utah State University. Logan, UT. USA."> <meta name="citation_author" content="Douglas Dickinson"> <meta name="citation_author_institution" content="Camellix Research Laboratory, Augusta, GA. USA."> <meta name="citation_author" content="Stephen Hsu"> <meta name="citation_author_institution" content="Camellix Research Laboratory, Augusta, GA. USA."> <meta name="citation_author_institution" content="Department of Oral Biology & Diagnostic Sciences, Augusta University, Augusta, GA. USA."> <meta name="citation_publication_date" content="2021"> <meta name="citation_volume" content="5"> <meta name="citation_issue" content="2"> <meta name="citation_firstpage" content="10.33425/2639-9458.1116"> <meta name="citation_doi" content="10.33425/2639-9458.1116"> <meta name="citation_pmid" content="35291211"> <meta name="citation_abstract_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/"> <meta name="citation_fulltext_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/"> <meta name="citation_pdf_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/pdf/nihms-1784119.pdf"> <meta name="description" content="SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic, caused >26 million cases in the United States and >437,000 deaths as of Jan 30, 2020. Worldwide by that date, there had been 102 million cases of infections, and deaths had ..."> <meta name="og:title" content="Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication)"> <meta name="og:type" content="article"> <meta name="og:site_name" content="PubMed Central (PMC)"> <meta name="og:description" content="SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic, caused >26 million cases in the United States and >437,000 deaths as of Jan 30, 2020. Worldwide by that date, there had been 102 million cases of infections, and deaths had ..."> <meta name="og:url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/"> <meta name="og:image" content="https://cdn.ncbi.nlm.nih.gov/pmc/cms/images/pmc-card-share.jpg?_=0"> <meta name="twitter:card" content="summary_large_image"> <meta name="twitter:site" content="@ncbi"> </head> <body > <a class="usa-skipnav " href="#main-content"> Skip to main content </a> <section class="usa-banner " aria-label="Official website of the United States government" > <div class="usa-accordion"> <header class="usa-banner__header"> <div class="usa-banner__inner"> <div class="grid-col-auto"> <img aria-hidden="true" class="usa-banner__header-flag" src="/static/img/us_flag.svg" alt="" /> </div> <div class="grid-col-fill tablet:grid-col-auto" aria-hidden="true"> <p class="usa-banner__header-text"> An official website of the United States government </p> <span class="usa-banner__header-action">Here's how you know</span> </div> <button type="button" class="usa-accordion__button usa-banner__button " aria-expanded="false" aria-controls="gov-banner-default" data-testid="storybook-django-banner" > <span class="usa-banner__button-text">Here's how you know</span> </button> </div> </header> <div class="usa-banner__content usa-accordion__content" id="gov-banner-default" hidden> <div class="grid-row grid-gap-lg"> <div class="usa-banner__guidance tablet:grid-col-6"> <img class="usa-banner__icon usa-media-block__img" src="/static/img/icon-dot-gov.svg" alt="" aria-hidden="true" /> <div class="usa-media-block__body"> <p> <strong>Official websites use .gov</strong> <br /> A <strong>.gov</strong> website belongs to an official government organization in the United States. </p> </div> </div> <div class="usa-banner__guidance tablet:grid-col-6"> <img class="usa-banner__icon usa-media-block__img" src="/static/img/icon-https.svg" alt="" aria-hidden="true" /> <div class="usa-media-block__body"> <p> <strong>Secure .gov websites use HTTPS</strong> <br /> A <strong>lock</strong> ( <span class="icon-lock"> <svg xmlns="http://www.w3.org/2000/svg" width="52" height="64" viewBox="0 0 52 64" class="usa-banner__lock-image" role="graphics-symbol" aria-labelledby="banner-lock-description" focusable="false"> <title id="banner-lock-title">Lock</title> <desc id="banner-lock-description"> Locked padlock icon </desc> <path fill="#000000" fill-rule="evenodd" d="M26 0c10.493 0 19 8.507 19 19v9h3a4 4 0 0 1 4 4v28a4 4 0 0 1-4 4H4a4 4 0 0 1-4-4V32a4 4 0 0 1 4-4h3v-9C7 8.507 15.507 0 26 0zm0 8c-5.979 0-10.843 4.77-10.996 10.712L15 19v9h22v-9c0-6.075-4.925-11-11-11z" /> </svg> </span>) or <strong>https://</strong> means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. </p> </div> </div> </div> </div> </div> </section> <div class="usa-overlay"> </div> <header class="usa-header usa-header--extended usa-header--wide" data-testid="header" data-header > <div class="ncbi-header"> <div class="ncbi-header__container"> <a class="ncbi-header__logo-container" href="/"> <img alt=" PMC home page " class="ncbi-header__logo-image" src="/static/img/ncbi-logos/nih-nlm-ncbi--white.svg" /> </a>  <button type="button" class="usa-menu-btn ncbi-header__hamburger-button " aria-label="Show menu" data-testid="navMenuButton" > <svg aria-hidden="true" class="ncbi-hamburger-icon" fill="none" focusable="false" height="21" viewBox="0 0 31 21" width="31" xmlns="http://www.w3.org/2000/svg"> <path clip-rule="evenodd" d="M0.125 20.75H30.875V17.3333H0.125V20.75ZM0.125 12.2083H30.875V8.79167H0.125V12.2083ZM0.125 0.25V3.66667H30.875V0.25H0.125Z" fill="#F1F1F1" fill-rule="evenodd" /> </svg> </button>  <div class="ncbi-header__desktop-buttons">  <button type="button" class="usa-button usa-button--unstyled ncbi-header__desktop-button " aria-expanded="false" aria-controls="search-field-desktop-navigation" aria-label="Show search overlay" data-testid="toggleSearchPanelButton" data-toggle-search-panel-button > <svg class="usa-icon " role="graphics-symbol" aria-hidden="true" > <use xlink:href="/static/img/sprite.svg#search" /> </svg> Search </button>  <div class="ncbi-header__login-dropdown"> <button type="button" class="usa-button usa-button--unstyled ncbi-header__desktop-button ncbi-header__login-dropdown-button " aria-expanded="false" aria-controls="login-dropdown-menu" aria-label="Show login menu" data-testid="toggleLoginMenuDropdown" data-desktop-login-button > <svg class="usa-icon " role="graphics-symbol" aria-hidden="true" > <use xlink:href="/static/img/sprite.svg#person" /> </svg> <span data-login-dropdown-text>Log in</span>  <svg class="usa-icon ncbi-header__login-dropdown-icon ncbi-header__login-dropdown-icon--expand-less ncbi-header__login-dropdown-icon--hidden" role="graphics-symbol" aria-hidden="true" data-login-dropdown-up-arrow> <use xlink:href="/static/img/sprite.svg#expand_less" /> </svg>  <svg class="usa-icon ncbi-header__login-dropdown-icon ncbi-header__login-dropdown-icon--expand-more ncbi-header__login-dropdown-icon--hidden" role="graphics-symbol" aria-hidden="true" data-login-dropdown-down-arrow> <use xlink:href="/static/img/sprite.svg#expand_more" /> </svg> </button>  <ul class="usa-nav__submenu ncbi-header__login-dropdown-menu" id="login-dropdown-menu" data-desktop-login-menu-dropdown hidden> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/myncbi/" class="usa-link " > Dashboard </a> </li> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/" class="usa-link " > Publications </a> </li> <li class="usa-nav__submenu-item">  <a href="https://www.ncbi.nlm.nih.gov/account/settings/" class="usa-link " > Account settings </a> </li> <li class="usa-nav__submenu-item"> <button type="button" class="usa-button usa-button--outline ncbi-header__login-dropdown-logout-button " data-testid="desktopLogoutButton" data-desktop-logout-button > Log out </button> </li> </ul> </div> </div> </div> </div>  <div class="ncbi-search-panel ncbi--show-only-at-desktop" data-testid="searchPanel" data-header-search-panel hidden> <div class="ncbi-search-panel__container"> <form action="https://www.ncbi.nlm.nih.gov/search/all/" aria-describedby="search-field-desktop-navigation-help-text" autocomplete="off" class="usa-search usa-search--big ncbi-search-panel__form" data-testid="form" method="GET" role="search"> <label class="usa-sr-only" data-testid="label" for="search-field-desktop-navigation"> Search… </label> <input class="usa-input" data-testid="textInput" id="search-field-desktop-navigation" name="term" placeholder="Search NCBI" type="search" value="" /> <button type="submit" class="usa-button " data-testid="button" > <span class="usa-search__submit-text"> Search NCBI </span> </button> </form> </div> </div> <nav aria-label="Primary navigation" class="usa-nav"> <p class="usa-sr-only" id="primary-navigation-sr-only-title"> Primary site navigation </p>  <button type="button" class="usa-nav__close ncbi-nav__close-button " aria-label="Close navigation menu" data-testid="navCloseButton" > <img src="/static/img/usa-icons/close.svg" alt="Close" /> </button>  <form class="usa-search usa-search--small ncbi--hide-at-desktop margin-top-6" role="search"> <label class="usa-sr-only" for="search-field"> Search </label> <input class="usa-input" id="search-field-mobile-navigation" type="search" placeholder="Search NCBI" name="search" /> <button type="submit" class="usa-button " >  <img src="data:image/svg+xml;base64,PHN2ZyB4bWxucz0iaHR0cDovL3d3dy53My5vcmcvMjAwMC9zdmciIGhlaWdodD0iMjQiIHZpZXdCb3g9IjAgMCAyNCAyNCIgd2lkdGg9IjI0Ij48cGF0aCBkPSJNMCAwaDI0djI0SDB6IiBmaWxsPSJub25lIi8+PHBhdGggZmlsbD0iI2ZmZiIgZD0iTTE1LjUgMTRoLS43OWwtLjI4LS4yN0E2LjQ3MSA2LjQ3MSAwIDAgMCAxNiA5LjUgNi41IDYuNSAwIDEgMCA5LjUgMTZjMS42MSAwIDMuMDktLjU5IDQuMjMtMS41N2wuMjcuMjh2Ljc5bDUgNC45OUwyMC40OSAxOWwtNC45OS01em0tNiAwQzcuMDEgMTQgNSAxMS45OSA1IDkuNVM3LjAxIDUgOS41IDUgMTQgNy4wMSAxNCA5LjUgMTEuOTkgMTQgOS41IDE0eiIvPjwvc3ZnPg==" class="usa-search__submit-icon" alt="Search" /> </button> </form>   <div class="ncbi-nav__mobile-login-menu ncbi--hide-at-desktop" data-mobile-login-menu hidden> <p class="ncbi-nav__mobile-login-menu-status"> Logged in as: <strong class="ncbi-nav__mobile-login-menu-email" data-mobile-login-email-text></strong> </p> <ul class="usa-nav__primary usa-accordion"> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/myncbi/" class="usa-link " > Dashboard </a> </li> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/" class="usa-link " > Publications </a> </li> <li class="usa-nav__primary-item"> <a href="https://www.ncbi.nlm.nih.gov/account/settings/" class="usa-link " > Account settings </a> </li> </ul> </div> <button type="button" class="usa-button ncbi-nav__mobile-login-button ncbi--hide-at-desktop " data-testid="mobileLoginButton" data-mobile-login-button > Log in </button> </nav> </header> <section class="pmc-header pmc-header--basic" aria-label="PMC Header with search box"> <div class="pmc-nav-container"> <div class="pmc-header__bar"> <div class="pmc-header__logo"> <a href="/" title="Home" aria-label="PMC Home"></a> </div> <button type="button" class="usa-button usa-button--unstyled pmc-header__search__button" aria-label="Open search" data-ga-category="search" data-ga-action="PMC" data-ga-label="pmc_search_panel_mobile" > <svg class="usa-icon width-4 height-4 pmc-icon__open" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#search"></use> </svg> <svg class="usa-icon width-4 height-4 pmc-icon__close" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#close"></use> </svg> </button> </div> <div class="pmc-header__search"> <form class="usa-search usa-search--extra usa-search--article-right-column pmc-header__search__form" autocomplete="off" role="search"> <label class="usa-sr-only" for="pmc-search">Search PMC Full-Text Archive</label> <span class="autoComplete_wrapper flex-1"> <input class="usa-input width-full maxw-none" required="required" placeholder="Search PMC Full-Text Archive" id="pmc-search" type="search" name="term" data-autocomplete-url="/search/autocomplete/"/> </span> <button class="usa-button" type="submit" formaction="https://www.ncbi.nlm.nih.gov/pmc/" data-ga-category="search" data-ga-action="PMC" data-ga-label="PMC_search_button" > <span class="usa-search__submit-text">Search in PMC</span> <img src="/static/img/usa-icons-bg/search--white.svg" class="usa-search__submit-icon" alt="Search" /> </button> </form> <ul class="pmc-header__search__menu"> <li> <a class="usa-link" href="https://www.ncbi.nlm.nih.gov/pmc/advanced/" data-ga-action="featured_link" data-ga-label="advanced_search"> Advanced Search </a> </li> <li> <a class="usa-link" href="/journals/" data-ga-action="featured_link" data-ga-label="journal list"> Journal List </a> </li> <li> <a class="usa-link" href="/about/userguide/" data-ga-action="featured_link" data-ga-label="user guide"> User Guide </a> </li> </ul> </div> </div> </section> <div class="usa-section padding-top-0 desktop:padding-top-6 pmc-article-section" data-article-db="pmc" data-article-id="8919953"> <div class="grid-container pmc-actions-bar" aria-label="Actions bar" role="complementary"> <div class="grid-row"> <div class="grid-col-fill display-flex"> <div class="display-flex"> <ul class="usa-list usa-list--unstyled usa-list--horizontal"> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex mob"> <button type="button" class="usa-button pmc-sidenav__container__open usa-button--unstyled width-auto display-flex" aria-label="Open resources" data-extra-class="is-visible-resources" data-ga-category="resources_accordion" data-ga-action="click" data-ga-label="mobile_icon" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#more_vert"></use> </svg> </button> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex mob"> <a href="https://doi.org/10.33425/2639-9458.1116" class="usa-link display-flex" role="button" target="_blank" rel="noreferrer noopener" aria-label="View on publisher site" data-ga-category="actions" data-ga-action="click" data-ga-label="publisher_link_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#launch"></use> </svg> </a> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <a href="pdf/nihms-1784119.pdf" class="usa-link display-flex" role="button" aria-label="Download PDF" data-ga-category="actions" data-ga-action="click" data-ga-label="pdf_download_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> </a> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <button class="usa-button usa-button--unstyled collections-dialog-trigger collections-button display-flex collections-button-empty" aria-label="Save article in MyNCBI collections." data-ga-category="actions" data-ga-action="click" data-ga-label="collections_button_mobile" data-collections-open-dialog-enabled="false" data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpmc.ncbi.nlm.nih.gov%2Farticles%2FPMC8919953%2F%23open-collections-dialog" data-in-collections="false" > <svg class="usa-icon width-4 height-4 usa-icon--bookmark-full" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-full.svg#icon"></use> </svg> <svg class="usa-icon width-4 height-4 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-empty.svg#icon"></use> </svg> </button> </li> <li class="margin-right-2 mobile-lg:margin-right-4 display-flex"> <button role="button" class="usa-button usa-button--unstyled citation-dialog-trigger display-flex" aria-label="Open dialog with citation text in different styles" data-ga-category="actions" data-ga-action="open" data-ga-label="cite_mobile" data-all-citations-url="/resources/citations/8919953/" data-citation-style="nlm" data-download-format-link="/resources/citations/8919953/export/" > <svg class="usa-icon width-4 height-4 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#format_quote"></use> </svg> </button> </li> <li class="pmc-permalink display-flex"> <button type="button" class="usa-button usa-button--unstyled display-flex" aria-label="Show article permalink" aria-expanded="false" aria-haspopup="true" data-ga-category="actions" data-ga-action="open" data-ga-label="permalink_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#share"></use> </svg> </button> <div class="pmc-permalink__dropdown" hidden> <div class="pmc-permalink__dropdown__container"> <h2 class="usa-modal__heading margin-top-0 margin-bottom-2">PERMALINK</h2> <div class="pmc-permalink__dropdown__content"> <input type="text" class="usa-input" value="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/" aria-label="Article permalink"> <button class="usa-button display-inline-flex pmc-permalink__dropdown__copy__btn margin-right-0" title="Copy article permalink" data-ga-category="save_share" data-ga-action="link" data-ga-label="copy_link"> <svg class="usa-icon" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span class="margin-left-1">Copy</span> </button> </div> </div> </div> </li> </ul> </div> <button type="button" class="usa-button pmc-sidenav__container__open usa-button--unstyled width-auto display-flex" aria-label="Open article navigation" data-extra-class="is-visible-in-page" data-ga-category="actions" data-ga-action="open" data-ga-label="article_nav_mobile" > <svg class="usa-icon width-4 height-4" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#list"></use> </svg> </button> </div> </div> </div> <div class="grid-container desktop:padding-left-6"> <div id="article-container" class="grid-row grid-gap"> <div class="grid-col-12 desktop:grid-col-8 order-2 pmc-layout__content"> <div class="grid-container padding-left-0 padding-right-0"> <div class="grid-row desktop:margin-left-neg-6"> <div class="grid-col-12"> <div class="pmc-layout__disclaimer" role="complementary" aria-label="Disclaimer note"> As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.<br/> Learn more: <a class="usa-link" data-ga-category="Link click" data-ga-action="Disclaimer" data-ga-label="New disclaimer box" href="/about/disclaimer/">PMC Disclaimer</a> | <a class="usa-link" data-ga-category="Link click" data-ga-action="PMC Copyright Notice" data-ga-label="New disclaimer box" href="/about/copyright/"> PMC Copyright Notice </a> </div> </div> </div> <div class="grid-row pmc-wm desktop:margin-left-neg-6">  <main id="main-content" class="usa-layout-docs__main usa-layout-docs grid-col-12 pmc-layout pmc-prose padding-0" > <section class="pmc-journal-banner text-center line-height-none" aria-label="Journal banner"><img src="https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-nihpa.png" alt="NIHPA Author Manuscripts logo" usemap="#pmc-banner-imagemap" width="500" height="75"><map name="pmc-banner-imagemap"><area alt="Link to NIHPA Author Manuscripts" title="Link to NIHPA Author Manuscripts" shape="default" href="https://www.hhs.gov/open/public-access-guiding-principles/index.html" target="_blank" rel="noopener noreferrer"></map></section><article lang="en"><section aria-label="Article citation and metadata"><section class="pmc-layout__citation font-secondary font-xs"><div> <div class="display-inline-block"><button type="button" class="cursor-pointer text-no-underline bg-transparent border-0 padding-0 text-left margin-0 text-normal text-primary" aria-controls="journal_context_menu">Microbiol Infect Dis</button></div>. Author manuscript; available in PMC: 2022 Mar 14.</div> <div> <em>Published in final edited form as: </em>Microbiol Infect Dis. 2021;5(2):10.33425/2639-9458.1116. doi: <a href="https://doi.org/10.33425/2639-9458.1116" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.33425/2639-9458.1116</a> </div> <nav id="journal_context_menu" hidden="hidden"><ul class="menu-list font-family-ui" role="menu"> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/pmc/?term=%22Microbiol%20Infect%20Dis%22%5Bjour%5D" class="usa-link" role="menuitem">Search in PMC</a></li> <li role="presentation"><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Microbiol%20Infect%20Dis%22%5Bjour%5D" lang="en" class="usa-link" role="menuitem">Search in PubMed</a></li> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Microbiol%20Infect%20Dis%22%5BTitle%20Abbreviation%5D" class="usa-link" role="menuitem">View in NLM Catalog</a></li> <li role="presentation"><a href="?term=%22Microbiol%20Infect%20Dis%22%5Bjour%5D" class="usa-link" role="menuitem" data-add-to-search="true">Add to search</a></li> </ul></nav></section><section class="front-matter"><div class="ameta p font-secondary font-xs"> <hgroup><h1>Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells</h1> <p>(A Short Communication)</p></hgroup><div class="cg p"> <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hurst%20BL%22%5BAuthor%5D" class="usa-link" aria-describedby="id1"><span class="name western">Brett L Hurst</span></a><div hidden="hidden" id="id1"> <h3><span class="name western">Brett L Hurst</span></h3> <div class="p"> <sup>1.</sup>Institute of Antiviral Research, Utah State University. Logan, UT. USA.</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hurst%20BL%22%5BAuthor%5D" class="usa-link"><span class="name western">Brett L Hurst</span></a> </div> </div> <sup>1</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dickinson%20D%22%5BAuthor%5D" class="usa-link" aria-describedby="id2"><span class="name western">Douglas Dickinson</span></a><div hidden="hidden" id="id2"> <h3><span class="name western">Douglas Dickinson</span></h3> <div class="p"> <sup>2.</sup>Camellix Research Laboratory, Augusta, GA. USA.</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Dickinson%20D%22%5BAuthor%5D" class="usa-link"><span class="name western">Douglas Dickinson</span></a> </div> </div> <sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hsu%20S%22%5BAuthor%5D" class="usa-link" aria-describedby="id3"><span class="name western">Stephen Hsu</span></a><div hidden="hidden" id="id3"> <h3><span class="name western">Stephen Hsu</span></h3> <div class="p"> <sup>2.</sup>Camellix Research Laboratory, Augusta, GA. USA.</div> <div class="p"> <sup>3.</sup>Department of Oral Biology & Diagnostic Sciences, Augusta University, Augusta, GA. USA.</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Hsu%20S%22%5BAuthor%5D" class="usa-link"><span class="name western">Stephen Hsu</span></a> </div> </div> <sup>2,</sup><sup>3,</sup><sup>*</sup> </div> <ul class="d-buttons inline-list"> <li><button class="d-button" aria-controls="aip_a" aria-expanded="false">Author information</button></li> <li><button class="d-button" aria-controls="clp_a" aria-expanded="false">Copyright and License information</button></li> </ul> <div class="d-panels font-secondary-light"> <div id="aip_a" class="d-panel p" style="display: none"> <div class="p" id="A1"> <sup>1.</sup>Institute of Antiviral Research, Utah State University. Logan, UT. USA.</div> <div id="A2"> <sup>2.</sup>Camellix Research Laboratory, Augusta, GA. USA.</div> <div id="A3"> <sup>3.</sup>Department of Oral Biology & Diagnostic Sciences, Augusta University, Augusta, GA. USA.</div> <div class="author-notes p"><div class="fn" id="CR1"> <sup>*</sup><p class="display-inline">Corresponding author Stephen Hsu, CB2404B, Augusta University, Department of Oral Biology & Diagnostic Sciences, Dental College of Georgia, augusta University, Augusta, GA 30912, USA, <span>shsu@augusta.edu</span></p> </div></div> </div> <div id="clp_a" class="d-panel p" style="display: none"><div class="p"><a href="/about/copyright/" class="usa-link">PMC Copyright notice</a></div></div> </div> <div>PMCID: PMC8919953 NIHMSID: NIHMS1784119 PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/35291211/" class="usa-link">35291211</a> </div> <div class="ra xbox p" role="complementary" aria-label="Related or updated information about this article"><div>The publisher's version of this article is available at <a href="https://doi.org/10.33425/2639-9458.1116" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Microbiol Infect Dis</a> </div></div> </div></section></section><section aria-label="Article content"><section class="body main-article-body"><section class="abstract" id="ABS1"><h2>Abstract</h2> <p id="P1">SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic, caused >26 million cases in the United States and >437,000 deaths as of Jan 30, 2020. Worldwide by that date, there had been 102 million cases of infections, and deaths had climbed to 2.21 million. Mutated variants of SARS-CoV-2 that have emerged from the United Kingdom, Brazil, and South Africa are associated with higher transmission rates and associated deaths. Therefore, novel therapeutic and prophylactic methods against SARS-CoV-2 are in urgent need. While some antiviral drugs, such as Remdesivir, provide relief to certain patient populations, other existing antiviral drugs or combinations of FDA approved pharmaceuticals have yet to show clinical efficacy against COVID-19. Compounds that possess strong and broad antiviral properties with different mechanisms of action against respiratory viruses may provide novel approaches to combat SARS-CoV-2 and its variants, especially if the compounds are classified as generally recognized as safe (GRAS). A large body of evidence indicates a promising potential for the use of epigallocatechin-3-gallate (EGCG) and its derivatives as effective agents against infections from a wide range of pathogenic viruses. However, EGCG or its derivatives have not been tested directly against SARS-CoV-2. The current study was designed to evaluate the potential antiviral activity of EGCG against SARS-CoV-2 infection in primate epithelial cells. Methods applied in the study include cytopathic effect (CPE) assay and virus yield reduction (VYR) assays using Vero 76 (green monkey epithelial cells) and Caco-2 (human epithelial cells) cell lines, respectively. The results demonstrated that EGCG at 0.27 μg/ml (0.59 μM) inhibited SARS-CoV-2 infection in Vero 76 cells by 50% (i.e., EC50=0.27 μg/ml). EGCG also inhibited SARS-CoV-2 infection in Caco-2 cells with EC90=28 μg/ml (61 μM). These results, to the best of our knowledge, are the first observations on the antiviral activities of EGCG against SARS-CoV-2, and suggest that EGCG and its derivatives could be used to combat COVID-19 and other respiratory viral infection-induced illness, pending <em>in vivo</em> and clinical studies.</p> <section id="kwd-group1" class="kwd-group"><p><strong>Keywords:</strong> Coronavirus, SARS-CoV-2, EGCG, Green Tea, Epithelial Cells</p></section></section><section id="S1"><h2 class="pmc_sec_title">Introduction</h2> <p id="P2">Previous studies indicated that EGCG, a major hydrophilic component of extracts from leaves of the <em>Camellia sinensis</em> (tea) plant, and its hydrophobic derivatives (especially EGCG-palmitate, or EC16), could be potential candidates for antiviral and virucidal material (<a href="#R1" class="usa-link" aria-describedby="R1">1</a>-<a href="#R19" class="usa-link" aria-describedby="R19">19</a>, reviewed in <a href="#R20" class="usa-link" aria-describedby="R20">20</a>). Importantly, EGCG and lipophilic EGCG (such as EC16) are classified as non-toxic food additives, considered by the US FDA as a generally recognized as safe (GRAS) food additive (FDA GRAS Notice 772).</p> <p id="P3">Accumulating data indicate that EGCG and its hydrophobic derivatives may fill gaps in the area of prevention and treatment of influenza virus infection, by multi-target mechanisms (<a href="#R21" class="usa-link" aria-describedby="R21">21</a>). EGCG inactivates virus particles by direct binding to viral coat proteins, and it inhibits viral-receptor binding, endosome formation and internalization, nuclear uptake, and transcription of the viral genome (<a href="#R22" class="usa-link" aria-describedby="R22">22</a>).</p> <p id="P4">EGCG at micromolar (μM) levels inhibits the infectivity of a diverse group of enveloped and non-enveloped viruses by interrupting viral attachment to cell membrane receptors (<a href="#R8" class="usa-link" aria-describedby="R8">8</a>). We reported that inactivation of HSV-1 was through non-specific binding of EGCG to viral surface proteins (<a href="#R18" class="usa-link" aria-describedby="R18">18</a>, <a href="#R19" class="usa-link" aria-describedby="R19">19</a>). EGCG at μM levels dose-dependently inhibited Ebola virus infectivity in human cells (<a href="#R9" class="usa-link" aria-describedby="R9">9</a>). Either green tea extract or pure EGCG inhibited the infectivity of hepatitis B virus (HBV) in HepG2-N10 cell culture (<a href="#R20" class="usa-link" aria-describedby="R20">20</a>). At concentrations as low as 0.002 μM, EGCG inhibited hepatitis C virus (HCV) entry into hepatoma cell lines and primary human hepatocytes, by interruption of viral attachment to host cells (<a href="#R20" class="usa-link" aria-describedby="R20">20</a>). Importantly, EGCG at physiologically achievable levels of 1 to 10 μg/mL (2.17-21.7 μM) effectively inhibited HCV cell-to-cell spread, making EGCG a potential solution to prevent and treat Hepatitis C (<a href="#R22" class="usa-link" aria-describedby="R22">22</a>). EGCG’s direct binding to the virion leads to a bulging of the viral envelope. This structural change of the virion might contribute to the loss of the virion’s ability to attach to cell surface receptors (<a href="#R21" class="usa-link" aria-describedby="R21">21</a>). This mechanism could also be responsible for preventing virion entry of HBV (<a href="#R23" class="usa-link" aria-describedby="R23">23</a>). EGCG shows high-affinity binding to CD4 protein, thereby inhibiting the binding of HIV vgp120 to human CD4<sup>+</sup> cells (<a href="#R24" class="usa-link" aria-describedby="R24">24</a>-<a href="#R26" class="usa-link" aria-describedby="R26">26</a>). EGCG binds to influenza A and B viral hemagglutinin (HA) and sialic acid on the cell membrane, and alters the membrane properties, leading to inhibition of viral entry (<a href="#R8" class="usa-link" aria-describedby="R8">8</a>, <a href="#R28" class="usa-link" aria-describedby="R28">28</a>-<a href="#R30" class="usa-link" aria-describedby="R30">30</a>). EGCG also binds to neuraminidase (NA), at a different binding site (residue 430) than other drugs, and reduces the activity of releasing new viral particles from infected cells (<a href="#R31" class="usa-link" aria-describedby="R31">31</a>, <a href="#R32" class="usa-link" aria-describedby="R32">32</a>). EGCG reduces viral replication by interfering with the association between viral dsRNA and NS1 by binding to NS1 protein (<a href="#R33" class="usa-link" aria-describedby="R33">33</a>). Importantly, in human nasal epithelial cells, the antioxidant activity of EGCG combined with upregulation of Nrf-2 expression contributes to inhibition of viral infection and replication, through EGCG-induced Nrf-2 expression significantly inhibiting viral entry (<a href="#R34" class="usa-link" aria-describedby="R34">34</a>). EGCG also has an inhibitory effect on influenza A RNA polymerase activity (<a href="#R35" class="usa-link" aria-describedby="R35">35</a>). Specific binding between EGCG and viral RNA polymerase has been confirmed, and EGCG was shown to chelate critical manganese ions in the active site of the enzyme (<a href="#R36" class="usa-link" aria-describedby="R36">36</a>). These properties could explain our data showing EGCG prevents H1N1 infection in cell culture (<a href="#R37" class="usa-link" aria-describedby="R37">37</a>). In addition, the antiviral properties of EGCG have a wide species spectrum, and EGCG has been shown to be effective against most human viruses tested (<a href="#R8" class="usa-link" aria-describedby="R8">8</a>).</p> <p id="P5">As a potent antioxidant, water-soluble EGCG is quickly self-oxidized in an oxygen-rich environment. Thus, it is difficult to maintain activity in a liquid formulation. Therefore, EGCG derivatives were studied to search for a candidate form of EGCG that was physically stable, and more active against viruses, which could be suitable for a new generation of EGCG-derived small molecules active against viral infections (<a href="#R38" class="usa-link" aria-describedby="R38">38</a>). A group of patented lipophilic EGCG compounds (US composition patent 8076484) has been tested in multiple <em>in vitro</em> and <em>in vivo</em> models. Kaihatsu’s group identified a lipid-soluble EGCG derivative, EGCG-palmitate (EC16), as the most active form of EGCG for influenza virus inactivation, being 44-fold more effective than hydrophilic EGCG (<a href="#R4" class="usa-link" aria-describedby="R4">4</a>). Similarly, previous studies from our group demonstrated that EC16 is more potent than EGCG for herpes simplex virus 1 (HSV-1) inactivation, and for herpes labialis, the clinical outcome from topical application of the EC16-containing formulation AverTeaX was more effective than other topical medications (<a href="#R11" class="usa-link" aria-describedby="R11">11</a>, <a href="#R12" class="usa-link" aria-describedby="R12">12</a>, <a href="#R19" class="usa-link" aria-describedby="R19">19</a>). We also found that the virucidal activity of EC16 lasted for several hours after a single application on a clean surface (<a href="#R39" class="usa-link" aria-describedby="R39">39</a>). Importantly, newly reported data from our group indicates that EC16 in a proprietary liquid formulation effectively protected MDCK epithelial cells from influenza virus infection (<a href="#R37" class="usa-link" aria-describedby="R37">37</a>). These green tea polyphenols are able to inhibit SARS-CoV TMPRSS2 (<a href="#R40" class="usa-link" aria-describedby="R40">40</a>, <a href="#R41" class="usa-link" aria-describedby="R41">41</a>), N protein (<a href="#R42" class="usa-link" aria-describedby="R42">42</a>, <a href="#R43" class="usa-link" aria-describedby="R43">43</a>), 3C-like protease (<a href="#R44" class="usa-link" aria-describedby="R44">44</a>, <a href="#R45" class="usa-link" aria-describedby="R45">45</a>), and these observations suggest a multi-targeted, and thus potentially mutation-proof, mechanism of action against viruses, potentially including coronavirus.</p> <p id="P6">In summary, the broad-spectrum of antiviral and virucidal properties of EGCG and EGCG-palmitate with multi-target mechanisms have been documented with encouraging efficacy results. The current study determined the potential antiviral activities of EGCG against SARS-CoV-2 infection in different primate cell lines.</p></section><section id="S2"><h2 class="pmc_sec_title">Material and Methods</h2> <p id="P7">EGCG was provided from the Research Laboratory of Camellix, LLC (Augusta University, Augusta, GA). All other materials and methods were provided through a non-clinical evaluation agreement (NCEA) between the National Institute of Allergy & Infectious Diseases (NIAID) and Augusta University/Camellix, LLC. The experiments were performed in the Institute for Antiviral Research, Utah State University. The cytotoxicity tests were performed using a standard test method that exposed the cell culture to EGCG for the entire test period of antiviral assays. This method aims to induce the maximum cytotoxic effect possible by EGCG. In contrast, the antiviral tests described below exposed the cells to EGCG for 1 hr.</p> <section id="S3"><h3 class="pmc_sec_title">Primary CPE assay – Vero 76 cells</h3> <p id="P8">Confluent or near-confluent cell culture monolayers of Vero 76 cells were prepared in 96-well disposable microplates the day before testing. Cells were maintained in Minimum Essential Media (MEM) supplemented with 5% fetal bovine serum (FBS). For antiviral assays the same medium was used but FBS was reduced to 2% and supplemented with 50-μg/ml gentamicin. EGCG was dissolved in serum-free MEM at four serial log<sub>10</sub> concentrations, usually 0.1, 1.0, 10, and 100 μg/ml. Five microwells were used per dilution: three for infected cultures and two for uninfected EGCG toxicity assessment. Controls for the experiment consist of six microwells that were infected and not treated (virus controls) and six that were untreated and uninfected (cell controls) on every plate.</p> <p id="P9">The dilutions of EGCG were incubated with SARS-CoV-2 (1:1) at ~60 CCID<sub>50</sub> (50% cell culture infectious dose) in 0.2 ml volume for 1 h prior to adding to the cell culture for 1 h absorption after removal of the growth media. The EGCG/SARS-CoV-2 mix was then removed and 0.2 ml fresh MEM with 2% FBS and 50-μg/ml gentamicin was added to the cell culture. Medium devoid of virus was placed in toxicity control wells and cell control wells. Plates were incubated at 37° C with 5% CO<sub>2</sub> until marked (> 80%) CPE was observed in virus control wells. The plates were then stained with 0.011% neutral red for approximately two hours at 37° C in a 5% CO<sub>2</sub> incubator. The neutral red medium was removed by complete aspiration, and the cells rinsed 1X with phosphate buffered solution (PBS) to remove residual dye. The PBS was completely removed, and the retained neutral red was eluted with 50% Sorensen’s citrate buffer/50% ethanol for at least 30 minutes. Neutral red dye penetrates into living cells, thus, the more intense the red color, the larger the number of viable cells present in the wells. The dye content in each well was quantified using a spectrophotometer at 540 nm wavelength, and dye content in each set of wells was converted to a percentage of dye present in untreated control wells using a Microsoft Excel computer-based spreadsheet and normalized based on the virus control. The 50% effective (EC<sub>50</sub>, virus-inhibitory) concentrations and 50% cytotoxic (CC<sub>50</sub>, cell-inhibitory) concentrations were then calculated by regression analysis. The quotient of CC<sub>50</sub> divided by EC<sub>50</sub> gives the selectivity index (SI) value.</p></section><section id="S4"><h3 class="pmc_sec_title">Secondary VYR assay - virus yield reduction – Caco-2 cells</h3> <p id="P10">The VYR assay is a direct determination of the ability of EGCG to inhibit virus entry and replication. Caco-2 cells were maintained in MEM supplemented with 10% FBS. EGCG was dissolved in serum-free MEM in a series of 2 x dilutions from 100 μg/ml down to 0.78 μg/ml, and dilutions were incubated with SARS-CoV-2 (1:1) at 200 CCID<sub>50</sub> (50% cell culture infectious dose) in 0.1 ml volume for 1 h prior to adding to the cell culture for 1 h absorption. The EGCG/SARS-CoV-2 mix was removed and fresh MEM was added to the cell culture with 2% FBS, 50-μg/ml gentamicin for viral yield detection in comparison to untreated infection control. Five microwells were used per dilution: three for infected cultures and two for uninfected toxicity tests. Controls for the experiment consisted of six microwells that were infected but not treated (virus controls) and six that were untreated and uninfected (cell controls) on every plate. After 72 h, supernatants from each set of three replicate infected wells were pooled and a sample was tested immediately in a viral yield reduction assay. Virus yield in the presence of EGCG was titrated and compared to virus titers from the untreated virus controls. Titration of the viral samples was performed by endpoint dilution: serial 1/10 dilutions of virus were made and plated into 4 replicate wells containing fresh cell monolayers of Vero 76 cells. Plates were then incubated, and cells were scored for the presence or absence of virus after distinct CPE was observed, and the CCID<sub>50</sub> calculated using the Reed-Muench method (<a href="#R47" class="usa-link" aria-describedby="R47">47</a>). The 90% (one log<sub>10</sub>) effective concentration (EC<sub>90</sub>) was calculated by regression analysis by plotting the log<sub>10</sub> of the inhibitor concentration versus log<sub>10</sub> of virus produced at each concentration. The quotient of CC<sub>50</sub> divided by EC<sub>90</sub> gives the selectivity index (SI) value.</p></section></section><section id="S5"><h2 class="pmc_sec_title">Results</h2> <section id="S6"><h3 class="pmc_sec_title">Primary CPE assay – Vero 76 cells</h3> <p id="P11">The cytopathic effect (CPE) assay results showed that EGCG inhibited 50% of SARS-CoV-2 infection in Vero cells at 0.27 μg/ml (i.e., EC50=0.000027% or 0.59 μM) (<a href="#T1" class="usa-link">Table 1</a>) after 1 hr exposure to EGCG, while 50% cytotoxicity (CC50) after the completion of antiviral assays (7-10 days) was apparent when the concentration of EGCG increased 8.5 times to 5.03 μM.</p> <section class="tw xbox font-sm" id="T1"><h4 class="obj_head">Table 1.</h4> <div class="caption p"><p id="P21">Inhibitory effects of EGCG on SARS-CoV-2 in two primate epithelial cells.</p></div> <div class="tbl-box p" tabindex="0"><table class="content" frame="box" rules="all"> <colgroup span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> </colgroup> <thead><tr> <th align="left" valign="top" rowspan="1" colspan="1">Vero 76 Cells</th> <th align="left" valign="top" rowspan="1" colspan="1">EC50</th> <th align="left" valign="top" rowspan="1" colspan="1">CC50</th> <th align="left" valign="top" rowspan="1" colspan="1">SI</th> </tr></thead> <tbody><tr> <td align="left" valign="top" rowspan="1" colspan="1"></td> <td align="left" valign="top" rowspan="1" colspan="1">0.59 μM</td> <td align="left" valign="top" rowspan="1" colspan="1">5.03 μM</td> <td align="left" valign="top" rowspan="1" colspan="1">8.5</td> </tr></tbody> <tbody> <tr> <th align="left" valign="top" rowspan="1" colspan="1">Caco-2 Cells</th> <th align="left" valign="top" rowspan="1" colspan="1">EC90</th> <th align="left" valign="top" rowspan="1" colspan="1">CC50</th> <th align="left" valign="top" rowspan="1" colspan="1">SI</th> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1"></td> <td align="left" valign="top" rowspan="1" colspan="1">61 μM</td> <td align="left" valign="top" rowspan="1" colspan="1">>217 μM</td> <td align="left" valign="top" rowspan="1" colspan="1">>3.6</td> </tr> </tbody> </table></div> <div class="p text-right font-secondary"><a href="table/T1/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div></section></section><section id="S7"><h3 class="pmc_sec_title">Secondary VYR assay - virus yield reduction – Caco-2 cells</h3> <p id="P12">The virus yield reduction (VYR)) assay results showed that EGCG inhibited 90% of SARS-CoV-2 infection in Caco-2 cells at 28 μg/ml (i.e., EC90=0.0028% or 61 μM) (<a href="#T1" class="usa-link">Table 1</a>), while 50% cytotoxicity (CC50) was not observed even when the EGCG concentration was increased to >100 μg/ml or 217 μM. Thus, the SI value could only be presented as >3.6 due to the low cytotoxicity of EGCG to Caco-2 cells.</p> <p id="P13">As shown in<a href="#T2" class="usa-link">Table 2</a>, EGCG at 50 μg/ml (0.005%), EGCG caused a further 1.8 log<sub>10</sub> reduction in viral titer in comparison to 12.5 μg EGCG, equivalent to a 98.41% reduction of viral yield in Caco-2 cells. At 100 μg/ml (0.01%), EGCG resulted in >3.6 log<sub>10</sub> reduction in virus titer in comparison to 12.5 μg EGCG, a >99.975% reduction of viral yield.</p> <section class="tw xbox font-sm" id="T2"><h4 class="obj_head">Table 2.</h4> <div class="caption p"><p id="P22">Viral titers of Caco-2 cell culture after SARS-CoV-2 infection in the present of EGCG for 1 h before EGCG/virus was removed. Raw data generated from virus yield reduction assay expressing dose-respons of EGCG-induced viral infection in TCID50 values.</p></div> <div class="tbl-box p" tabindex="0"><table class="content" frame="box" rules="all"> <colgroup span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> </colgroup> <thead><tr> <th align="left" valign="top" rowspan="1" colspan="1">EGCG concentration (μg/ml)</th> <th align="left" valign="top" rowspan="1" colspan="1">Viral titer of EGCG-treated Cell Culture<br>TCID50 in log<sub>10</sub> values</th> </tr></thead> <tbody> <tr> <td align="left" valign="top" rowspan="1" colspan="1">100</td> <td align="left" valign="top" rowspan="1" colspan="1"><1.7</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">50</td> <td align="left" valign="top" rowspan="1" colspan="1">3.5</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">25</td> <td align="left" valign="top" rowspan="1" colspan="1">5.0</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">12.5</td> <td align="left" valign="top" rowspan="1" colspan="1">5.3</td> </tr> </tbody> </table></div> <div class="p text-right font-secondary"><a href="table/T2/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div></section></section></section><section id="S8"><h2 class="pmc_sec_title">Discussion</h2> <p id="P14">The cytopathic effect (CPE) assay results showed that after a 1 hr exposure, EGCG was effective and blocked 50% of SARS-CoV-2 infection in Vero 76 cells at a very low concentration of 0.000027% (0.59 μM). Prolonged exposure to EGCG induced cytotoxicity in Vero 76 cells at 0.00023% or 5.03 μM, a near 10-fold higher concentration. However, this concentration of EGCG-associated cytotoxicity in Vero 76 cells was somewhat lower than previously published data. For example, our group reported that after 48 h incubation with 50 μM EGCG, cell proliferation rate was reduced to 79.68% in Vero cells (parental cell line of Vero 76 cells) (<a href="#R19" class="usa-link" aria-describedby="R19">19</a>). This inconsistency could be due to the different assay methods, culture conditions and/or cell lines used.</p> <p id="P15">In contrast, the observed CC50 for EGCG in Caco-2 cells, a cell line derived from human intestinal epithelial cells (colorectal adenocarcinoma), was >217 μM of EGCG, consistent with previously published data in human cells showing low cytotoxicity.</p> <p id="P16">In general, EGCG and its derivatives are considered safe for oral and topical applications for human use. A group of patented lipophilic EGCG derivatives (US 8076484) has been tested in multiple <em>in vitro</em> and <em>in vivo</em> models without apparent toxicity (<a href="#R11" class="usa-link" aria-describedby="R11">11</a>, <a href="#R12" class="usa-link" aria-describedby="R12">12</a>, <a href="#R19" class="usa-link" aria-describedby="R19">19</a>, <a href="#R48" class="usa-link" aria-describedby="R48">48</a>, <a href="#R49" class="usa-link" aria-describedby="R49">49</a>). In 2019, the US FDA approved the use of tea catechins palmitate (containing approximately 50% EGCG-palmitate) as a GRAS (generally recognized as safe) dietary ingredient (FDA GRAS Notice 772, Ref <a href="#R50" class="usa-link" aria-describedby="R50">50</a>). It was found that tea catechin palmitate undergoes hydrolysis after consumption, consistent with our findings that EGCG-fatty esters are hydrolyzed to free EGCG after entering cells (<a href="#R5" class="usa-link" aria-describedby="R5">5</a>). These studies concluded that the intended use of tea catechin palmitate meets the GRAS requirement (<a href="#R50" class="usa-link" aria-describedby="R50">50</a>). Indeed, our previous data demonstrated that a 1 h incubation of Vero cells with 50 μM EGCG-palmitate only reduced cell viability by 0.043%, and reduced the cell growth by 10.91% after 48 h incubation (<a href="#R19" class="usa-link" aria-describedby="R19">19</a>). Of note, the antiviral activity against herpes simplex virus 1 (HSV-1) of EGCG-palmitate is significantly higher than that of EGCG – 100% vs. 92.15% (<a href="#R19" class="usa-link" aria-describedby="R19">19</a>). This difference in antiviral activity between EGCG-palmitate and EGCG was also reported by others (<a href="#R3" class="usa-link" aria-describedby="R3">3</a>).</p> <p id="P17">Currently, methods that could be effective against novel pathogenic respiratory viruses such as SARS-CoV-2 or other types of or mutated coronavirus are not available. There is an urgent need to develop a fast acting, efficacious, economical strategy with a completely different mechanism of action to protect airway epithelial cells from viral entry; with multiple targets for effect against viral entry and replication and thereby potentially mutation-proof; agents to rapidly inactivate a broad-spectrum of respiratory viruses; and agents with the above properties but without toxic side effect.</p> <p id="P18">Since the major point of host entry for SARS-CoV-2 is <em>via</em> nasal epithelial cells, intranasal-applied therapeutics could be highly effective (<a href="#R51" class="usa-link" aria-describedby="R51">51</a>). Based on <em>in vitro</em> and <em>in vivo</em> evidence, we hypothesize that EGCG and its hydrophobic derivatives possess strong antiviral activity against human coronaviruses, with potential to become therapeutic and prophylactic agents against infections of SARS-CoV-2 and its mutants. While the mechanisms of SARS-CoV-2 transmission are still under investigation, aerosol transmission is a known significant route for viral entry to infect humans (<a href="#R51" class="usa-link" aria-describedby="R51">51</a>). Our previous studies demonstrated that EGCG in a formulation suitable for nasal application is effective against influenza virus H1N1 (<a href="#R37" class="usa-link" aria-describedby="R37">37</a>).</p> <p id="P19">Here we report, for the first time according to the best of our knowledge, that EGCG is able to inhibit SARS-CoV-2 infection in primate epithelial cells, include human cells, at doses not associate with toxicity. These results demonstrate that this class of compounds derived from green tea leaf extracts are potential agents for new drug development against a wide spectrum of respiratory viruses, including novel coronavirus and its mutated variants, pending further investigations.</p></section><section id="S9" class="ack"><h2 class="pmc_sec_title">Acknowledgement</h2> <p id="P20">The authors thank Augusta University Research Institute and the National Institute of Allergy and Infectious Diseases for their support. Augusta Research Institute and Camellix Research Laboratory have utilized the non-clinical services program offered by the National Institute of Allergy and Infectious Diseases.</p></section><section id="ref-list1" class="ref-list"><h2 class="pmc_sec_title">References Cited</h2> <section id="ref-list1_sec2"><ul class="ref-list font-sm" style="list-style-type:none"> <li id="R1"> <span class="label">1.</span><cite>Matsumoto Y, Kaihatsu K, Nishino K, Ogawa M, Kato N, Yamaguchi A. Antibacterial and antifungal activities of new acylated derivatives of epigallocatechin gallate. Front Microbiol. 2012; 3: 53.</cite> [<a href="https://doi.org/10.3389/fmicb.2012.00053" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3280433/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22355295/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Front%20Microbiol&title=Antibacterial%20and%20antifungal%20activities%20of%20new%20acylated%20derivatives%20of%20epigallocatechin%20gallate&author=Y%20Matsumoto&author=K%20Kaihatsu&author=K%20Nishino&author=M%20Ogawa&author=N%20Kato&volume=3&publication_year=2012&pages=53&pmid=22355295&doi=10.3389/fmicb.2012.00053&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R2"> <span class="label">2.</span><cite>Zhao C, Liu S, Li C, Yang L, Zu Y. In vitro evaluation of the antiviral activity of the synthetic epigallocatechin gallate analog-epigallocatechin gallate (EGCG) palmitate against porcine reproductive and respiratory syndrome virus. Viruses. 2014; 6: 938–950.</cite> [<a href="https://doi.org/10.3390/v6020938" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3939490/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24566281/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Viruses&title=In%20vitro%20evaluation%20of%20the%20antiviral%20activity%20of%20the%20synthetic%20epigallocatechin%20gallate%20analog-epigallocatechin%20gallate%20(EGCG)%20palmitate%20against%20porcine%20reproductive%20and%20respiratory%20syndrome%20virus&author=C%20Zhao&author=S%20Liu&author=C%20Li&author=L%20Yang&author=Y%20Zu&volume=6&publication_year=2014&pages=938-950&pmid=24566281&doi=10.3390/v6020938&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R3"> <span class="label">3.</span><cite>Mori S, Miyake S, Kobe T, Nakaya T, Fuller SD, Kato N, Kaihatsu K. Enhanced anti-influenza A virus activity of (−)-epigallocatechin-3-O-gallate fatty acid monoester derivatives: effect of alkyl chain length. Bioorg Med Chem Lett. 2008; 18: 4249–4252.</cite> [<a href="https://doi.org/10.1016/j.bmcl.2008.02.020" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18547804/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Bioorg%20Med%20Chem%20Lett&title=Enhanced%20anti-influenza%20A%20virus%20activity%20of%20(%E2%88%92)-epigallocatechin-3-O-gallate%20fatty%20acid%20monoester%20derivatives:%20effect%20of%20alkyl%20chain%20length&author=S%20Mori&author=S%20Miyake&author=T%20Kobe&author=T%20Nakaya&author=SD%20Fuller&volume=18&publication_year=2008&pages=4249-4252&pmid=18547804&doi=10.1016/j.bmcl.2008.02.020&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R4"> <span class="label">4.</span><cite>Paterson I, Anderson EA. The renaissance of natural products as drug candidates. Science. 2005; 310: 451–453.</cite> [<a href="https://doi.org/10.1126/science.1116364" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16239465/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Science&title=The%20renaissance%20of%20natural%20products%20as%20drug%20candidates&author=I%20Paterson&author=EA%20Anderson&volume=310&publication_year=2005&pages=451-453&pmid=16239465&doi=10.1126/science.1116364&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R5"> <span class="label">5.</span><cite>Hsu S, and Dickinson D. Green tea and skin protection: mechanism of action and practical applications. Household and Personal Care. 2009; 33–36.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Household%20and%20Personal%20Care&title=Green%20tea%20and%20skin%20protection:%20mechanism%20of%20action%20and%20practical%20applications&author=S%20Hsu&author=D%20Dickinson&publication_year=2009&pages=33-36&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R6"> <span class="label">6.</span><cite>Chen P, Dickinson D, and Hsu S. Lipid-soluble Green Tea Polyphenols: Stabilized for Effective Formulation. In: Handbook of Green Tea and Health Research. ISBN 978-1-60741-045-4 Editor: McKinley H and Jamieson M, Nova Science Publishers, Inc. 2009.</cite> [<a href="https://scholar.google.com/scholar_lookup?title=Handbook%20of%20Green%20Tea%20and%20Health%20Research&author=P%20Chen&author=D%20Dickinson&author=S%20Hsu&author=H%20McKinley&author=M%20Jamieson&publication_year=2009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R7"> <span class="label">7.</span><cite>Steinmann J, Buer J, Pietschmann T, Steinmann E. Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. Br J Pharmacol. 2013; 168: 1059–1073.</cite> [<a href="https://doi.org/10.1111/bph.12009" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3594666/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23072320/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Br%20J%20Pharmacol&title=Anti-infective%20properties%20of%20epigallocatechin-3-gallate%20(EGCG),%20a%20component%20of%20green%20tea&author=J%20Steinmann&author=J%20Buer&author=T%20Pietschmann&author=E%20Steinmann&volume=168&publication_year=2013&pages=1059-1073&pmid=23072320&doi=10.1111/bph.12009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R8"> <span class="label">8.</span><cite>Colpitts CC, Schang LM. A small molecule inhibits virion attachment to heparan sulfate- or sialic acid-containing glycans. J Virol. 2014; 88: 7806–7817.</cite> [<a href="https://doi.org/10.1128/JVI.00896-14" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4097786/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24789779/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Virol&title=A%20small%20molecule%20inhibits%20virion%20attachment%20to%20heparan%20sulfate-%20or%20sialic%20acid-containing%20glycans&author=CC%20Colpitts&author=LM%20Schang&volume=88&publication_year=2014&pages=7806-7817&pmid=24789779&doi=10.1128/JVI.00896-14&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R9"> <span class="label">9.</span><cite>Reid SP, Shurtleff AC,, Costantino JA, Tritsch SR, Retterer C, Spurgers KB, Bavari S. HSPA5 is an essential host factor for Ebola virus infection. Antiviral Res. 2014; 109: 171–174.</cite> [<a href="https://doi.org/10.1016/j.antiviral.2014.07.004" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25017472/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Antiviral%20Res&title=HSPA5%20is%20an%20essential%20host%20factor%20for%20Ebola%20virus%20infection&author=SP%20Reid&author=AC%20Shurtleff&author=JA%20Costantino&author=SR%20Tritsch&author=C%20Retterer&volume=109&publication_year=2014&pages=171-174&pmid=25017472&doi=10.1016/j.antiviral.2014.07.004&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R10"> <span class="label">10.</span><cite>De Rossi SS, Thoppay J, Dickinson DP, Looney S, Stuart M, Ogbureke KU, Hsu S. A phase II clinical trial of a natural formulation containing tea catechins for xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014; 118: 447–454.</cite> [<a href="https://doi.org/10.1016/j.oooo.2014.06.015" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25240992/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Oral%20Surg%20Oral%20Med%20Oral%20Pathol%20Oral%20Radiol&title=A%20phase%20II%20clinical%20trial%20of%20a%20natural%20formulation%20containing%20tea%20catechins%20for%20xerostomia&author=SS%20De%20Rossi&author=J%20Thoppay&author=DP%20Dickinson&author=S%20Looney&author=M%20Stuart&volume=118&publication_year=2014&pages=447-454&pmid=25240992&doi=10.1016/j.oooo.2014.06.015&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R11"> <span class="label">11.</span><cite>Zhao M, Jiang J, Zheng R, Fu B, Pearl H, Dickinson D, and Hsu S. A proprietary topical preparation containing EGCG-stearate and glycerin with inhibitory effects on herpes simplex virus: case report. Inflammation & Allergy – Drug Targets. 2012; 11: 364–368.</cite> [<a href="https://doi.org/10.2174/187152812803251033" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22583482/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Inflammation%20&%20Allergy%20%E2%80%93%20Drug%20Targets&title=A%20proprietary%20topical%20preparation%20containing%20EGCG-stearate%20and%20glycerin%20with%20inhibitory%20effects%20on%20herpes%20simplex%20virus:%20case%20report&author=M%20Zhao&author=J%20Jiang&author=R%20Zheng&author=B%20Fu&author=H%20Pearl&volume=11&publication_year=2012&pages=364-368&pmid=22583482&doi=10.2174/187152812803251033&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R12"> <span class="label">12.</span><cite>Zhao M, Zheng R, Jiang J, Dickinson D, Fu B, Chu T, Lee L, Pearl H, and Hsu S. Topical Lipophilic EGCG on Herpes Labialis: A Phase II Clinical Trial of AverTeaX. OOOO, 2015; 120: 717–724.</cite> [<a href="https://doi.org/10.1016/j.oooo.2015.08.018" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26548726/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=OOOO&title=Topical%20Lipophilic%20EGCG%20on%20Herpes%20Labialis:%20A%20Phase%20II%20Clinical%20Trial%20of%20AverTeaX&author=M%20Zhao&author=R%20Zheng&author=J%20Jiang&author=D%20Dickinson&author=B%20Fu&volume=120&publication_year=2015&pages=717-724&pmid=26548726&doi=10.1016/j.oooo.2015.08.018&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R13"> <span class="label">13.</span><cite>Chen P, Wang H, Du Q, Ito Y. Purification of long-chain fatty acid ester of epigallocatechin-3- O-gallate by high-speed counter-current chromatography. J Chromatogr A. 2002; 982:163–165.</cite> [<a href="https://doi.org/10.1016/s0021-9673(02)01604-7" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12489865/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Chromatogr%20A&title=Purification%20of%20long-chain%20fatty%20acid%20ester%20of%20epigallocatechin-3-%20O-gallate%20by%20high-speed%20counter-current%20chromatography&author=P%20Chen&author=H%20Wang&author=Q%20Du&author=Y%20Ito&volume=982&publication_year=2002&pages=163-165&pmid=12489865&doi=10.1016/s0021-9673(02)01604-7&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R14"> <span class="label">14.</span><cite>Chen P, Tan Y, Sun D, Zheng XM. A novel long-chain acyl-derivative of epigallocatechin-3-O- gallate prepared and purified from green tea polyphenols. J Zhejiang Univ Sci. 2003; 4: 714–8.</cite> [<a href="https://doi.org/10.1631/jzus.2003.0714" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14566988/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Zhejiang%20Univ%20Sci&title=A%20novel%20long-chain%20acyl-derivative%20of%20epigallocatechin-3-O-%20gallate%20prepared%20and%20purified%20from%20green%20tea%20polyphenols&author=P%20Chen&author=Y%20Tan&author=D%20Sun&author=XM%20Zheng&volume=4&publication_year=2003&pages=714-8&pmid=14566988&doi=10.1631/jzus.2003.0714&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R15"> <span class="label">15.</span><cite>Chen P, Sun D. A new catechin derivative as antioxidant for vegetable oil. Journal of the Chinese Cereals and oils association. 2003; 18:5: 77–78.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Journal%20of%20the%20Chinese%20Cereals%20and%20oils%20association&title=A%20new%20catechin%20derivative%20as%20antioxidant%20for%20vegetable%20oil&author=P%20Chen&author=D%20Sun&volume=18&issue=5&publication_year=2003&pages=77-78&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R16"> <span class="label">16.</span><cite>Sun D, Zhang S, Zhu Y, Wang Y. Study on antioxidant activity of lipid-soluble tea polyphenol in lipid. Cereals & Oil (Chinese). 2014; 27:1:42</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Cereals%20&%20Oil%20(Chinese)&title=Study%20on%20antioxidant%20activity%20of%20lipid-soluble%20tea%20polyphenol%20in%20lipid&author=D%20Sun&author=S%20Zhang&author=Y%20Zhu&author=Y%20Wang&volume=27&issue=1&publication_year=2014&pages=42&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R17"> <span class="label">17.</span><cite>Ryu S, You HJ, Kim YW, Lee A, Ko GP, Lee SJ, Song MJ. Inactivation of norovirus and surrogates by natural phytochemicals and bioactive substances. Mol Nutr Food Res. 2015; 59: 65–74.</cite> [<a href="https://doi.org/10.1002/mnfr.201400549" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25410634/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Mol%20Nutr%20Food%20Res&title=Inactivation%20of%20norovirus%20and%20surrogates%20by%20natural%20phytochemicals%20and%20bioactive%20substances&author=S%20Ryu&author=HJ%20You&author=YW%20Kim&author=A%20Lee&author=GP%20Ko&volume=59&publication_year=2015&pages=65-74&pmid=25410634&doi=10.1002/mnfr.201400549&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R18"> <span class="label">18.</span><cite>Hsu S. Compounds derived from epigallocatechin-3-gallate (EGCG) as a novel approach to the prevention of viral infections. Inflammation & Allergy - Drug Target. 2015; 14: 13–18.</cite> [<a href="https://doi.org/10.2174/1871528114666151022150122" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26490660/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Inflammation%20&%20Allergy%20-%20Drug%20Target&title=Compounds%20derived%20from%20epigallocatechin-3-gallate%20(EGCG)%20as%20a%20novel%20approach%20to%20the%20prevention%20of%20viral%20infections&author=S%20Hsu&volume=14&publication_year=2015&pages=13-18&pmid=26490660&doi=10.2174/1871528114666151022150122&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R19"> <span class="label">19.</span><cite>de Oliveira A, Adams SD, Lee LH, Murray SR, Hsu SD, Hammond JR, Dickinson D, Chen P, Chu TC. Inhibition of herpes simplex virus type 1 with the modified green tea polyphenol palmitoyl-epigallocatechin gallate. Food Chem Toxicol. 2012; 52: 207–215.</cite> [<a href="https://doi.org/10.1016/j.fct.2012.11.006" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3703635/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23182741/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Food%20Chem%20Toxicol&title=Inhibition%20of%20herpes%20simplex%20virus%20type%201%20with%20the%20modified%20green%20tea%20polyphenol%20palmitoyl-epigallocatechin%20gallate&author=A%20de%20Oliveira&author=SD%20Adams&author=LH%20Lee&author=SR%20Murray&author=SD%20Hsu&volume=52&publication_year=2012&pages=207-215&pmid=23182741&doi=10.1016/j.fct.2012.11.006&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R20"> <span class="label">20.</span><cite>Xu J, Xu Z, Zheng W. A Review of the Antiviral Role of Green Tea Catechins. Molecules. 2017; 22: 1337.</cite> [<a href="https://doi.org/10.3390/molecules22081337" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC6152177/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28805687/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Molecules&title=A%20Review%20of%20the%20Antiviral%20Role%20of%20Green%20Tea%20Catechins&author=J%20Xu&author=Z%20Xu&author=W%20Zheng&volume=22&publication_year=2017&pages=1337&pmid=28805687&doi=10.3390/molecules22081337&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R21"> <span class="label">21.</span><cite>Calland N, Sahuc ME, Belouzard S, Pène V, Bonnafous P, Mesalam AA, Deloison G, Descamps V, Sahpaz S, Wychowski C, Lambert O, Brodin P, Duverlie G, Meuleman P, Rosenberg AR, Dubuisson J, Rouillé Y, Séron K. Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action. J Virol. 2015; 89: 10053–63</cite> [<a href="https://doi.org/10.1128/JVI.01473-15" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC4577911/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26202241/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Virol&title=Polyphenols%20Inhibit%20Hepatitis%20C%20Virus%20Entry%20by%20a%20New%20Mechanism%20of%20Action&author=N%20Calland&author=ME%20Sahuc&author=S%20Belouzard&author=V%20P%C3%A8ne&author=P%20Bonnafous&volume=89&publication_year=2015&pages=10053-63&pmid=26202241&doi=10.1128/JVI.01473-15&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R22"> <span class="label">22.</span><cite>Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J, Manns MP, Ott M, Wedemeyer H, Meuleman P, Pietschmann T, Steinmann E. The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry. Hepatology. 2011; 54: 1947–55.</cite> [<a href="https://doi.org/10.1002/hep.24610" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21837753/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Hepatology&title=The%20green%20tea%20polyphenol,%20epigallocatechin-3-gallate,%20inhibits%20hepatitis%20C%20virus%20entry&author=S%20Ciesek&author=T%20von%20Hahn&author=CC%20Colpitts&author=LM%20Schang&author=M%20Friesland&volume=54&publication_year=2011&pages=1947-55&pmid=21837753&doi=10.1002/hep.24610&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R23"> <span class="label">23.</span><cite>Huang HC, Tao MH, Hung TM, Chen JC, Lin ZJ, Huang C. (−)Epigallocatechin-3-gallate inhibits entry of hepatitis B virus into hepatocytes. Antiviral Res., 2014; 111: 100–111.</cite> [<a href="https://doi.org/10.1016/j.antiviral.2014.09.009" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25260897/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Antiviral%20Res&title=(%E2%88%92)Epigallocatechin-3-gallate%20inhibits%20entry%20of%20hepatitis%20B%20virus%20into%20hepatocytes&author=HC%20Huang&author=MH%20Tao&author=TM%20Hung&author=JC%20Chen&author=ZJ%20Lin&volume=111&publication_year=2014&pages=100-111&pmid=25260897&doi=10.1016/j.antiviral.2014.09.009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R24"> <span class="label">24.</span><cite>Williamson MP, McCormick TG, Nance CL, Shearer WT. Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy. J Allergy Clin Immunol. 2006; 118: 1369–1374.</cite> [<a href="https://doi.org/10.1016/j.jaci.2006.08.016" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17157668/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Epigallocatechin%20gallate,%20the%20main%20polyphenol%20in%20green%20tea,%20binds%20to%20the%20T-cell%20receptor,%20CD4:%20Potential%20for%20HIV-1%20therapy&author=MP%20Williamson&author=TG%20McCormick&author=CL%20Nance&author=WT%20Shearer&volume=118&publication_year=2006&pages=1369-1374&pmid=17157668&doi=10.1016/j.jaci.2006.08.016&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R25"> <span class="label">25.</span><cite>Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa K, Asakage M, Hori N, Watanabe T, Takahashi K, Nagawa H. Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding. J Allergy Clin Immunol. 2003; 112: 951–957.</cite> [<a href="https://doi.org/10.1016/s0091-6749(03)02007-4" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14610487/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Epigallocatechin%20gallate,%20the%20main%20component%20of%20tea%20polyphenol,%20binds%20to%20CD4%20and%20interferes%20with%20gp120%20binding&author=K%20Kawai&author=NH%20Tsuno&author=J%20Kitayama&author=Y%20Okaji&author=K%20Yazawa&volume=112&publication_year=2003&pages=951-957&pmid=14610487&doi=10.1016/s0091-6749(03)02007-4&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R26"> <span class="label">26.</span><cite>Nance CL, Siwak EB, Shearer WT. Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J Allergy Clin Immunol. 2009; 123: 459–465.</cite> [<a href="https://doi.org/10.1016/j.jaci.2008.12.024" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC2665796/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19203663/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Allergy%20Clin%20Immunol&title=Preclinical%20development%20of%20the%20green%20tea%20catechin,%20epigallocatechin%20gallate,%20as%20an%20HIV-1%20therapy&author=CL%20Nance&author=EB%20Siwak&author=WT%20Shearer&volume=123&publication_year=2009&pages=459-465&pmid=19203663&doi=10.1016/j.jaci.2008.12.024&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R27"> <span class="label">27.</span><cite>Huang JL, Yan C, Liu XW, et al. Progress of research on the effect of epigallocatechin-3- gallate against influenza virus. Chinese Journal of Virology. 2018; 34: 259–263.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Chinese%20Journal%20of%20Virology&title=Progress%20of%20research%20on%20the%20effect%20of%20epigallocatechin-3-%20gallate%20against%20influenza%20virus&author=JL%20Huang&author=C%20Yan&author=XW%20Liu&volume=34&publication_year=2018&pages=259-263&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R28"> <span class="label">28..</span><cite>Kim M, Kim SY, Lee HW, Shin JS, Kim P, Jung YS, Jeong HS, Hyun JK, Lee CK. Inhibition of influenza virus internalization by (−)-epigallocatechin-3-gallate. Antiviral Res. 2013; 100: 460–472.</cite> [<a href="https://doi.org/10.1016/j.antiviral.2013.08.002" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23954192/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Antiviral%20Res&title=Inhibition%20of%20influenza%20virus%20internalization%20by%20(%E2%88%92)-epigallocatechin-3-gallate&author=M%20Kim&author=SY%20Kim&author=HW%20Lee&author=JS%20Shin&author=P%20Kim&volume=100&publication_year=2013&pages=460-472&pmid=23954192&doi=10.1016/j.antiviral.2013.08.002&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R29"> <span class="label">29.</span><cite>Ge H, Liu G, Xiang YF, Wang Y, Guo CW, Chen NH, Zhang YJ, Wang YF, Kitazato K, Xu J. The mechanism of poly-galloyl-glucoses preventing Influenza A virus entry into host cells. PLoS One. 2014; 9: e94392.</cite> [<a href="https://doi.org/10.1371/journal.pone.0094392" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3981784/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24718639/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20One&title=The%20mechanism%20of%20poly-galloyl-glucoses%20preventing%20Influenza%20A%20virus%20entry%20into%20host%20cells&author=H%20Ge&author=G%20Liu&author=YF%20Xiang&author=Y%20Wang&author=CW%20Guo&volume=9&publication_year=2014&pages=e94392&pmid=24718639&doi=10.1371/journal.pone.0094392&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R30"> <span class="label">30.</span><cite>Koszalka P, Danielle Tilmanis D, and Hurt A. Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir Viruses. 2017; 11: 240–246.</cite> [<a href="https://doi.org/10.1111/irv.12446" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC5410715/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28146320/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Influenza%20Other%20Respir%20Viruses&title=Influenza%20antivirals%20currently%20in%20late-phase%20clinical%20trial&author=P%20Koszalka&author=D%20Danielle%20Tilmanis&author=A%20Hurt&volume=11&publication_year=2017&pages=240-246&pmid=28146320&doi=10.1111/irv.12446&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R31"> <span class="label">31.</span><cite>Song JM, Lee KH, Seong BL. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res. 2005; 68: 66–74.</cite> [<a href="https://doi.org/10.1016/j.antiviral.2005.06.010" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16137775/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Antiviral%20Res&title=Antiviral%20effect%20of%20catechins%20in%20green%20tea%20on%20influenza%20virus&author=JM%20Song&author=KH%20Lee&author=BL%20Seong&volume=68&publication_year=2005&pages=66-74&pmid=16137775&doi=10.1016/j.antiviral.2005.06.010&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R32"> <span class="label">32.</span><cite>Müller P, Downard KM. Catechin inhibition of influenza neuraminidase and its molecular basis with mass spectrometry. J Pharm Biomed Anal. 2015; 111: 222–230.</cite> [<a href="https://doi.org/10.1016/j.jpba.2015.03.014" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25910046/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Pharm%20Biomed%20Anal&title=Catechin%20inhibition%20of%20influenza%20neuraminidase%20and%20its%20molecular%20basis%20with%20mass%20spectrometry&author=P%20M%C3%BCller&author=KM%20Downard&volume=111&publication_year=2015&pages=222-230&pmid=25910046&doi=10.1016/j.jpba.2015.03.014&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R33"> <span class="label">33.</span><cite>Cho EJ, Xia S, Ma LC, Robertus J, Krug RM, Anslyn EV, Montelione GT, Ellington AD. Identification of influenza virus inhibitors targeting NS1A utilizing fluorescence polarization- based high-throughput assay. J Biomol Screen. 2012; 17: 448–59.</cite> [<a href="https://doi.org/10.1177/1087057111431488" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22223052/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Biomol%20Screen&title=Identification%20of%20influenza%20virus%20inhibitors%20targeting%20NS1A%20utilizing%20fluorescence%20polarization-%20based%20high-throughput%20assay&author=EJ%20Cho&author=S%20Xia&author=LC%20Ma&author=J%20Robertus&author=RM%20Krug&volume=17&publication_year=2012&pages=448-59&pmid=22223052&doi=10.1177/1087057111431488&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R34"> <span class="label">34.</span><cite>Kesic MJ, Simmons SO, Bauer R, Jaspers I. Nrf2 expression modifies influenza A entry and replication in nasal epithelial cells. Free Radic Biol Med. 2011; 51: 444–53.</cite> [<a href="https://doi.org/10.1016/j.freeradbiomed.2011.04.027" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3135631/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21549835/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Free%20Radic%20Biol%20Med&title=Nrf2%20expression%20modifies%20influenza%20A%20entry%20and%20replication%20in%20nasal%20epithelial%20cells&author=MJ%20Kesic&author=SO%20Simmons&author=R%20Bauer&author=I%20Jaspers&volume=51&publication_year=2011&pages=444-53&pmid=21549835&doi=10.1016/j.freeradbiomed.2011.04.027&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R35"> <span class="label">35.</span><cite>Kuzuhara T, Iwai Y, Takahashi H, et al. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr. 2009; 1:RRN1052.</cite> [<a href="https://doi.org/10.1371/currents.RRN1052" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC2762814/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20025206/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20Curr&title=Green%20tea%20catechins%20inhibit%20the%20endonuclease%20activity%20of%20influenza%20A%20virus%20RNA%20polymerase&author=T%20Kuzuhara&author=Y%20Iwai&author=H%20Takahashi&volume=1&publication_year=2009&pages=RRN1052&pmid=20025206&doi=10.1371/currents.RRN1052&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R36"> <span class="label">36.</span><cite>Kowalinski E, Zubieta C, Wolkerstorfer A, et al. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathog. 2012; 8: e1002831.</cite> [<a href="https://doi.org/10.1371/journal.ppat.1002831" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3410856/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22876177/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20Pathog&title=Structural%20analysis%20of%20specific%20metal%20chelating%20inhibitor%20binding%20to%20the%20endonuclease%20domain%20of%20influenza%20pH1N1%20(2009)%20polymerase&author=E%20Kowalinski&author=C%20Zubieta&author=A%20Wolkerstorfer&volume=8&publication_year=2012&pages=e1002831&pmid=22876177&doi=10.1371/journal.ppat.1002831&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R37"> <span class="label">37.</span><cite>Dickinson D, Xayaraj S, Dickinson S, Shao X and Hsu S. Effect of Novel Formulations using Lipophilic Epigallocatechin-3-Gallate against Influenza Virus Infection. Microbiology & Infectious Diseases, 2018; 2: 1–8.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Microbiology%20&%20Infectious%20Diseases&title=Effect%20of%20Novel%20Formulations%20using%20Lipophilic%20Epigallocatechin-3-Gallate%20against%20Influenza%20Virus%20Infection&author=D%20Dickinson&author=S%20Xayaraj&author=S%20Dickinson&author=X%20Shao&author=S%20Hsu&volume=2&publication_year=2018&pages=1-8&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R38"> <span class="label">38.</span><cite>Ping C, Dickinson D, Hsu S Lipid-soluble green tea polyphenols: potentials for health care and consumer products. Green Tea and Health Research. In McKinley Helen and Jamieson Mark (Eds.). Handbook of Green Tea and Health Research. 45-61. Nova Publishers; 2009; 45–61.</cite> [<a href="https://scholar.google.com/scholar_lookup?title=Handbook%20of%20Green%20Tea%20and%20Health%20Research&author=C%20Ping&author=D%20Dickinson&author=S%20Hsu&author=Helen%20McKinley&author=Mark%20Jamieson&publication_year=2009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R39"> <span class="label">39.</span><cite>Widjaja N, Dickinson D, Shao X, et al. Persistent Virucidal Activity in Novel Alcohol-Based Sanitizer Formulation (ProtecTeaV) for Potential Use Against Norovirus. Microbiology & Infectious Diseases, 2018; 2: 1–8.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Microbiology%20&%20Infectious%20Diseases&title=Persistent%20Virucidal%20Activity%20in%20Novel%20Alcohol-Based%20Sanitizer%20Formulation%20(ProtecTeaV)%20for%20Potential%20Use%20Against%20Norovirus&author=N%20Widjaja&author=D%20Dickinson&author=X%20Shao&volume=2&publication_year=2018&pages=1-8&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R40"> <span class="label">40.</span><cite>Kesic Matthew J., Meyer Megan, Bauer Rebecca, Jaspers Ilona. Exposure to Ozone Modulates Human Airway Protease/Antiprotease Balance Contributing to Increased Influenza A Infection. PLoS One. 2012; 7: e35108.</cite> [<a href="https://doi.org/10.1371/journal.pone.0035108" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3322171/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22496898/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=PLoS%20One&title=Exposure%20to%20Ozone%20Modulates%20Human%20Airway%20Protease/Antiprotease%20Balance%20Contributing%20to%20Increased%20Influenza%20A%20Infection&author=Matthew%20J.%20Kesic&author=Megan%20Meyer&author=Rebecca%20Bauer&author=Ilona%20Jaspers&volume=7&publication_year=2012&pages=e35108&pmid=22496898&doi=10.1371/journal.pone.0035108&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R41"> <span class="label">41.</span><cite>Matthew Zirui Tay Chek Meng Poh, Laurent Rénia Paul A. MacAry, Ng Lisa F. P.. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020; 28 : 1–12.</cite> [<a href="https://doi.org/10.1038/s41577-020-0311-8" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC7187672/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32346093/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Immunol&title=The%20trinity%20of%20COVID-19:%20immunity,%20inflammation%20and%20intervention&author=Chek%20Meng%20Poh%20Matthew%20Zirui%20Tay&author=Paul%20A.%20MacAry%20Laurent%20R%C3%A9nia&author=Lisa%20F.%20P.%20Ng&volume=28&publication_year=2020&pages=1-12&pmid=32346093&doi=10.1038/s41577-020-0311-8&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R42"> <span class="label">42.</span><cite>Roh Changhyun. A facile inhibitor screening of SARS coronavirus N protein using nanoparticle-based RNA oligonucleotide. Int J Nanomedicine. 2012; 7: 2173–2179.</cite> [<a href="https://doi.org/10.2147/IJN.S31379" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC3356205/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22619553/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Int%20J%20Nanomedicine&title=A%20facile%20inhibitor%20screening%20of%20SARS%20coronavirus%20N%20protein%20using%20nanoparticle-based%20RNA%20oligonucleotide&author=Changhyun%20Roh&volume=7&publication_year=2012&pages=2173-2179&pmid=22619553&doi=10.2147/IJN.S31379&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R43"> <span class="label">43.</span><cite>Kang Sisi, Yang Mei, Hong Zhongsi, Zhang Liping, Huang Zhaoxia, Chen Xiaoxue, He Suhua, Zhou Ziliang, Zhou Zhechong, Chen Qiuyue, Yan Yan, Zhang Changsheng, Shan Hong, Chen Shoudeng. Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites. Acta Pharm Sin B. 2020; 10: 1228–1238.</cite> [<a href="https://doi.org/10.1016/j.apsb.2020.04.009" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC7194921/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32363136/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Acta%20Pharm%20Sin%20B&title=Crystal%20structure%20of%20SARS-CoV-2%20nucleocapsid%20protein%20RNA%20binding%20domain%20reveals%20potential%20unique%20drug%20targeting%20sites&author=Sisi%20Kang&author=Mei%20Yang&author=Zhongsi%20Hong&author=Liping%20Zhang&author=Zhaoxia%20Huang&volume=10&publication_year=2020&pages=1228-1238&pmid=32363136&doi=10.1016/j.apsb.2020.04.009&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R44"> <span class="label">44.</span><cite>Nguyen TTH, Woo HJ, Kang HK, Nguyen VD, Kim YM, Kim DW, Ahn SA, Xia Y, Kim D. Flavonoid-mediated inhibition of SARS coronavirus 3C like protease expressed in <em>Pichia pastoris</em>. Biotechnol Lett. 2012; 34: 831–838.</cite> [<a href="https://doi.org/10.1007/s10529-011-0845-8" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC7087583/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22350287/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Biotechnol%20Lett&title=Flavonoid-mediated%20inhibition%20of%20SARS%20coronavirus%203C%20like%20protease%20expressed%20in%20Pichia%20pastoris&author=TTH%20Nguyen&author=HJ%20Woo&author=HK%20Kang&author=VD%20Nguyen&author=YM%20Kim&volume=34&publication_year=2012&pages=831-838&pmid=22350287&doi=10.1007/s10529-011-0845-8&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R45"> <span class="label">45.</span><cite>Adhikari N, Baidya SK, Saha A, Jha T. Structural Insight Into the Viral 3C-Like Protease Inhibitors: Comparative SAR/QSAR Approaches. Viral Proteases and Their Inhibitors. 2017; 317–409.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Viral%20Proteases%20and%20Their%20Inhibitors&title=Structural%20Insight%20Into%20the%20Viral%203C-Like%20Protease%20Inhibitors:%20Comparative%20SAR/QSAR%20Approaches&author=N%20Adhikari&author=SK%20Baidya&author=A%20Saha&author=T%20Jha&publication_year=2017&pages=317-409&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R46"> <span class="label">46.</span><cite>Goldenberg G, Taylor M, Berman B, Kaufmann M, Abramovits W, Zeichner J. Sinecatechins Ointment, 15% for the Treatment of External Genital and Perianal Warts: Proceedings of an Expert Panel Roundtable Meeting. J Clin Aesthet Dermatol. 2016; 9(3 Suppl 1): S2–S15</cite> [<a href="/articles/PMC5964656/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29844847/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Aesthet%20Dermatol&title=Sinecatechins%20Ointment,%2015%%20for%20the%20Treatment%20of%20External%20Genital%20and%20Perianal%20Warts:%20Proceedings%20of%20an%20Expert%20Panel%20Roundtable%20Meeting&author=G%20Goldenberg&author=M%20Taylor&author=B%20Berman&author=M%20Kaufmann&author=W%20Abramovits&volume=9&issue=3%20Suppl%201&publication_year=2016&pages=S2-S15&pmid=29844847&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R47"> <span class="label">47.</span><cite>Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Epidemiol. 1938; 27: 493–497.</cite> [<a href="https://scholar.google.com/scholar_lookup?journal=Am%20J%20Epidemiol&title=A%20simple%20method%20of%20estimating%20fifty%20per%20cent%20endpoints&author=LJ%20Reed&author=H%20Muench&volume=27&publication_year=1938&pages=493-497&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R48"> <span class="label">48.</span><cite>Zhou F, Xu S, Shen T, Xu YY, Khor SC, Li J, Ge J, Zheng YF, Hsu S, De Stefano J, Yang J, Xu LH, Zhu XQ. Antioxidant effects of lipophilic tea polyphenols on diethylnitrosamine/phenobarbital–induced hepatocarcinogenesis in rats. In Vivo, 2014; 28: 495–503.</cite> [<a href="https://pubmed.ncbi.nlm.nih.gov/24982215/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=In%20Vivo&title=Antioxidant%20effects%20of%20lipophilic%20tea%20polyphenols%20on%20diethylnitrosamine/phenobarbital%E2%80%93induced%20hepatocarcinogenesis%20in%20rats&author=F%20Zhou&author=S%20Xu&author=T%20Shen&author=YY%20Xu&author=SC%20Khor&volume=28&publication_year=2014&pages=495-503&pmid=24982215&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R49"> <span class="label">49.</span><cite>Shen T, Xu S, Zhou F, Duan T, Xu YY, Zheng YF, Hsu S, De Stefano J, Yang J, Xu LH, Zhu XQ. Chemoprevention by lipid-soluble tea polyphenols in DEN/PB induced hepatic precancerous lesions. Anticancer Research. 2014; 34: 683–93.</cite> [<a href="https://pubmed.ncbi.nlm.nih.gov/24511000/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Anticancer%20Research&title=Chemoprevention%20by%20lipid-soluble%20tea%20polyphenols%20in%20DEN/PB%20induced%20hepatic%20precancerous%20lesions&author=T%20Shen&author=S%20Xu&author=F%20Zhou&author=T%20Duan&author=YY%20Xu&volume=34&publication_year=2014&pages=683-93&pmid=24511000&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> <li id="R50"> <span class="label">50.</span><cite>USFDA GRAS Notice 772: GRAS Notice for Oil-Soluble Green Tea Extract (Green Tea Catechin Palmitate). 2019. PDF: <a href="https://www.fda.gov/media/126906/download" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.fda.gov/media/126906/download</a>. FDA “no question (approval)” letter: <a href="https://www.fda.gov/media/120299/download" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">https://www.fda.gov/media/120299/download</a></cite> </li> <li id="R51"> <span class="label">51.</span><cite>Sungnak W, Huang N, Bécavin C, Berg M, HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine. 2020; 26: 681–687.</cite> [<a href="https://doi.org/10.1038/s41591-020-0868-6" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">DOI</a>] [<a href="/articles/PMC8637938/" class="usa-link">PMC free article</a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32327758/" class="usa-link">PubMed</a>] [<a href="https://scholar.google.com/scholar_lookup?journal=Nature%20Medicine&title=HCA%20Lung%20Biological%20Network.%20SARS-CoV-2%20entry%20factors%20are%20highly%20expressed%20in%20nasal%20epithelial%20cells%20together%20with%20innate%20immune%20genes&author=W%20Sungnak&author=N%20Huang&author=C%20B%C3%A9cavin&author=M%20Berg&volume=26&publication_year=2020&pages=681-687&pmid=32327758&doi=10.1038/s41591-020-0868-6&" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</li> </ul></section></section></section></section></article> </main> </div> </div> </div>  <div class="pmc-sidenav desktop:grid-col-4 display-flex"> <section class="pmc-sidenav__container" aria-label="Article resources and navigation"> <button type="button" class="usa-button pmc-sidenav__container__close usa-button--unstyled"> <img src="/static/img/usa-icons/close.svg" role="img" alt="Close" /> </button> <div class="display-none desktop:display-block"> <section class="margin-top-4 desktop:margin-top-0"> <h2 class="margin-top-0">ACTIONS</h2> <ul class="usa-list usa-list--unstyled usa-list--actions"> <li> <a href="https://doi.org/10.33425/2639-9458.1116" class="usa-button usa-button--outline width-24 font-xs usa-link--external padding-left-0 padding-right-0" target="_blank" rel="noreferrer noopener" data-ga-category="actions" data-ga-action="click" data-ga-label="publisher_link_desktop" > <span class="height-3 display-inline-flex flex-align-center">View on publisher site</span> </a> </li> <li> <a href="pdf/nihms-1784119.pdf" class="usa-button usa-button--outline width-24 display-inline-flex flex-align-center flex-justify-start padding-left-1" data-ga-category="actions" data-ga-action="click" data-ga-label="pdf_download_desktop" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1">PDF (68.9 KB)</span> </a> </li> <li> <button role="button" class="usa-button width-24 citation-dialog-trigger display-inline-flex flex-align-center flex-justify-start padding-left-1" aria-label="Open dialog with citation text in different styles" data-ga-category="actions" data-ga-action="open" data-ga-label="cite_desktop" data-all-citations-url="/resources/citations/8919953/" data-citation-style="nlm" data-download-format-link="/resources/citations/8919953/export/" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#format_quote"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1 button-label">Cite</span> </button> </li> <li> <button class="usa-button width-24 collections-dialog-trigger collections-button display-inline-flex flex-align-center flex-justify-start padding-left-1 collections-button-empty" aria-label="Save article in MyNCBI collections." data-ga-category="actions" data-ga-action="click" data-ga-label="collections_button_desktop" data-collections-open-dialog-enabled="false" data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpmc.ncbi.nlm.nih.gov%2Farticles%2FPMC8919953%2F%23open-collections-dialog" data-in-collections="false"> <svg class="usa-icon width-3 height-3 usa-icon--bookmark-full" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-full.svg#icon"></use> </svg> <svg class="usa-icon width-3 height-3 usa-icon--bookmark-empty" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/action-bookmark-empty.svg#icon"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1">Collections</span> </button> </li> <li class="pmc-permalink"> <button type="button" class="usa-button usa-button--outline width-24 display-inline-flex flex-align-center flex-justify padding-left-1 shadow-none" aria-label="Show article permalink" aria-expanded="false" aria-haspopup="true" data-ga-category="actions" data-ga-action="open" data-ga-label="permalink_desktop" > <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img" hidden> <use xlink:href="/static/img/sprite.svg#share"></use> </svg> <span class="display-inline-flex flex-justify-center flex-1 button-label">Permalink</span> </button> <div class="pmc-permalink__dropdown" hidden> <div class="pmc-permalink__dropdown__container"> <h2 class="usa-modal__heading margin-top-0 margin-bottom-2">PERMALINK</h2> <div class="pmc-permalink__dropdown__content"> <input type="text" class="usa-input" value="https://pmc.ncbi.nlm.nih.gov/articles/PMC8919953/" aria-label="Article permalink"> <button class="usa-button display-inline-flex pmc-permalink__dropdown__copy__btn margin-right-0" title="Copy article permalink" data-ga-category="save_share" data-ga-action="link" data-ga-label="copy_link"> <svg class="usa-icon" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span class="margin-left-1">Copy</span> </button> </div> </div> </div> </li> </ul> </section> </div> <section class="pmc-resources margin-top-6 desktop:margin-top-4" data-page-path="/articles/PMC8919953/"> <h2 class="margin-top-0">RESOURCES</h2> <div class="usa-accordion usa-accordion--multiselectable" data-allow-multiple> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-similar-articles" data-ga-category="resources_accordion" data-ga-action="open_similar_articles" data-ga-label="/articles/PMC8919953/" data-action-open="open_similar_articles" data-action-close="close_similar_articles" > Similar articles </button> </h3> <div id="resources-similar-articles" class="usa-accordion__content usa-prose" data-source-url="/resources/similar-article-links/35291211/" > </div> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-cited-by-other-articles" data-ga-category="resources_accordion" data-ga-action="open_cited_by" data-ga-label="/articles/PMC8919953/" data-action-open="open_cited_by" data-action-close="close_cited_by" > Cited by other articles </button> </h3> <div id="resources-cited-by-other-articles" class="usa-accordion__content usa-prose" data-source-url="/resources/cited-by-links/35291211/" > </div> <h3 class="usa-accordion__heading"> <button type="button" class="usa-accordion__button" aria-expanded="false" aria-controls="resources-links-to-ncbi-databases" data-ga-category="resources_accordion" data-ga-action="open_NCBI_links" data-ga-label="/articles/PMC8919953/" data-action-open="open_NCBI_links" data-action-close="close_NCBI_link" > Links to NCBI Databases </button> </h3> <div id="resources-links-to-ncbi-databases" class="usa-accordion__content usa-prose" data-source-url="/resources/db-links/8919953/" > </div> </div> </section> <section class="usa-in-page-nav usa-in-page-nav--wide margin-top-6 desktop:margin-top-4" data-title-text="On this page" data-title-heading-level="h2" data-scroll-offset="0" data-root-margin="-10% 0px -80% 0px" data-main-content-selector="main" data-threshold="1" hidden ></section> </section> </div> <div class="overlay" role="dialog" aria-label="Citation Dialog" hidden> <div class="dialog citation-dialog" aria-hidden="true"> <div class="display-inline-flex flex-align-center flex-justify width-full margin-bottom-2"> <h2 class="usa-modal__heading margin-0">Cite</h2> <button type="button" class="usa-button usa-button--unstyled close-overlay text-black width-auto" tabindex="1"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#close"></use> </svg> </button> </div> <div class="citation-text-block"> <div class="citation-text margin-bottom-2"></div> <ul class="usa-list usa-list--unstyled display-inline-flex flex-justify width-full flex-align-center"> <li> <button class="usa-button usa-button--unstyled text-no-underline display-flex flex-align-center copy-button dialog-focus" data-ga-category="save_share" data-ga-action="cite" data-ga-label="copy" tabindex="2"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#content_copy"></use> </svg> <span>Copy</span> </button> </li> <li> <a href="#" role="button" class="usa-button usa-button--unstyled text-no-underline display-flex flex-align-center export-button" data-ga-category="save_share" data-ga-action="cite" data-ga-label="download" title="Download a file for external citation management software" tabindex="3"> <svg class="usa-icon width-3 height-3" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#file_download"></use> </svg> <span class="display-none mobile-lg:display-inline">Download .nbib</span> <span class="display-inline mobile-lg:display-none">.nbib</span> </a> </li> <li> <div class="display-inline-flex flex-align-center"> <label class="usa-label margin-top-0">Format:</label> <select aria-label="Format" class="usa-select citation-style-selector padding-1 margin-top-0 border-0 padding-right-4" tabindex="4" > <option data-style-url-name="ama" value="AMA" > AMA </option> <option data-style-url-name="apa" value="APA" > APA </option> <option data-style-url-name="mla" value="MLA" > MLA </option> <option data-style-url-name="nlm" value="NLM" selected="selected"> NLM </option> </select> </div> </li> </ul> </div> </div> </div> <div class="overlay" role="dialog" hidden> <div id="collections-action-dialog" class="dialog collections-dialog" aria-hidden="true"> <div class="display-inline-flex flex-align-center flex-justify width-full margin-bottom-2"> <h2 class="usa-modal__heading margin-0">Add to Collections</h2> </div> <div class="collections-action-panel action-panel"> <form id="collections-action-dialog-form" class="usa-form maxw-full collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-existing-collections-url="/list-existing-collections/" data-add-to-existing-collection-url="/add-to-existing-collection/" data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/" data-myncbi-max-collection-name-length="100" data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"> <input type="hidden" name="csrfmiddlewaretoken" value="Cp1jjrRyFJp59s70qrcIO7wBHxlpvJ0bPyjWoWAA3SpLiiWZB62Vtnjmrr5Z6WNe"> <fieldset class="usa-fieldset margin-bottom-2"> <div class="usa-radio"> <input type="radio" id="collections-action-dialog-new" class="usa-radio__input usa-radio__input--tile collections-new margin-top-0" name="collections" value="new" data-ga-category="collections_button" data-ga-action="click" data-ga-label="collections_radio_new" /> <label class="usa-radio__label" for="collections-action-dialog-new">Create a new collection</label> </div> <div class="usa-radio"> <input type="radio" id="collections-action-dialog-existing" class="usa-radio__input usa-radio__input--tile collections-existing" name="collections" value="existing" checked="true" data-ga-category="collections_button" data-ga-action="click" data-ga-label="collections_radio_existing" /> <label class="usa-radio__label" for="collections-action-dialog-existing">Add to an existing collection</label> </div> </fieldset> <fieldset class="usa-fieldset margin-bottom-2"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-dialog-add-to-new" class="usa-label margin-top-0"> Name your collection <abbr title="required" class="usa-hint usa-hint--required text-no-underline">*</abbr> </label> <input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="usa-input collections-action-add-to-new" pattern="[^"&=<>/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection" required /> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-dialog-add-to-existing" class="usa-label margin-top-0"> Choose a collection </label> <select id="collections-action-dialog-add-to-existing" class="usa-select collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </fieldset> <div class="display-inline-flex"> <button class="usa-button margin-top-0 action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button> <button class="usa-button usa-button--outline margin-top-0 action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> </div> </div> </div> </div> <footer class="ncbi-footer ncbi-dark-background " > <div class="ncbi-footer__icon-section"> <div class="ncbi-footer__social-header"> Follow NCBI </div> <div class="grid-container ncbi-footer__ncbi-social-icons-container"> <a href="https://twitter.com/ncbi" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="40" height="40" viewBox="0 0 40 40" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="m6.067 8 10.81 13.9L6 33.2h4.2l8.4-9.1 7.068 9.1H34L22.8 18.5 31.9 8h-3.5l-7.7 8.4L14.401 8H6.067Zm3.6 1.734h3.266l16.8 21.732H26.57L9.668 9.734Z"> </path> </svg> <span class="usa-sr-only">NCBI on X (formerly known as Twitter)</span> </a> <a href="https://www.facebook.com/ncbi.nlm" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="16" height="29" focusable="false" aria-hidden="true" viewBox="0 0 16 29" fill="none" xmlns="http://www.w3.org/2000/svg"> <path d="M3.8809 21.4002C3.8809 19.0932 3.8809 16.7876 3.8809 14.478C3.8809 14.2117 3.80103 14.1452 3.54278 14.1492C2.53372 14.1638 1.52334 14.1492 0.514288 14.1598C0.302626 14.1598 0.248047 14.0972 0.248047 13.8936C0.256034 12.4585 0.256034 11.0239 0.248047 9.58978C0.248047 9.37013 0.302626 9.30224 0.528931 9.3049C1.53798 9.31688 2.54837 9.3049 3.55742 9.31555C3.80103 9.31555 3.8809 9.26097 3.87957 9.00272C3.87158 8.00565 3.85428 7.00592 3.90753 6.00884C3.97142 4.83339 4.31487 3.73115 5.04437 2.78467C5.93095 1.63318 7.15699 1.09005 8.56141 0.967577C10.5582 0.79319 12.555 0.982221 14.5518 0.927641C14.7102 0.927641 14.7462 0.99287 14.7449 1.13664C14.7449 2.581 14.7449 4.02668 14.7449 5.47104C14.7449 5.67604 14.6517 5.68669 14.4946 5.68669C13.4523 5.68669 12.4113 5.68669 11.3703 5.68669C10.3506 5.68669 9.92057 6.10868 9.90593 7.13904C9.89661 7.7647 9.91525 8.39303 9.89794 9.01869C9.88995 9.26364 9.96583 9.31822 10.2015 9.31688C11.7204 9.30623 13.2393 9.31688 14.7595 9.3049C15.0257 9.3049 15.0723 9.3728 15.0444 9.62439C14.89 10.9849 14.7515 12.3467 14.6144 13.7085C14.5691 14.1571 14.5785 14.1585 14.1458 14.1585C12.8386 14.1585 11.5313 14.1665 10.2254 14.1518C9.95119 14.1518 9.89794 14.2317 9.89794 14.4899C9.90593 19.0799 9.89794 23.6752 9.91125 28.2612C9.91125 28.5674 9.8407 28.646 9.53186 28.6433C7.77866 28.6273 6.02414 28.6366 4.27094 28.634C3.82499 28.634 3.87158 28.6992 3.87158 28.22C3.87602 25.9472 3.87913 23.6739 3.8809 21.4002Z"> </path> </svg> <span class="usa-sr-only">NCBI on Facebook</span> </a> <a href="https://www.linkedin.com/company/ncbinlm" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="25" height="23" viewBox="0 0 26 24" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M14.6983 9.98423C15.6302 9.24808 16.5926 8.74754 17.6762 8.51991C19.673 8.09126 21.554 8.30824 23.1262 9.7526C24.2351 10.7723 24.7529 12.1115 25.0165 13.5612C25.1486 14.3363 25.2105 15.1218 25.2015 15.9081C25.2015 18.3043 25.2015 20.6898 25.2082 23.0806C25.2082 23.3468 25.1549 23.444 24.8621 23.4414C23.1297 23.4272 21.3992 23.4272 19.6704 23.4414C19.4041 23.4414 19.3429 23.3588 19.3442 23.1019C19.3535 20.5194 19.3442 17.9368 19.3442 15.3543C19.3442 14.0005 18.3258 12.9448 17.0266 12.9488C15.7273 12.9528 14.6983 14.0071 14.6983 15.361C14.6983 17.9328 14.6917 20.5047 14.6983 23.0753C14.6983 23.3708 14.6198 23.444 14.3296 23.4427C12.6185 23.4294 10.9079 23.4294 9.19779 23.4427C8.93155 23.4427 8.86099 23.3735 8.86232 23.1086C8.8783 19.7619 8.88628 16.4144 8.88628 13.066C8.88628 11.5688 8.87874 10.0708 8.86365 8.57182C8.86365 8.3575 8.90758 8.27896 9.14054 8.28029C10.9048 8.29094 12.6687 8.29094 14.4321 8.28029C14.6464 8.28029 14.6983 8.34818 14.6983 8.54653C14.6903 9.00047 14.6983 9.45441 14.6983 9.98423Z"> </path> <path d="M6.55316 15.8443C6.55316 18.2564 6.55316 20.6699 6.55316 23.082C6.55316 23.3629 6.48127 23.4388 6.19906 23.4374C4.47737 23.4241 2.75568 23.4241 1.03399 23.4374C0.767751 23.4374 0.69986 23.3629 0.701191 23.1006C0.709178 18.2648 0.709178 13.4281 0.701191 8.59053C0.701191 8.34026 0.765089 8.27237 1.01669 8.2737C2.74991 8.28435 4.48048 8.28435 6.20838 8.2737C6.47462 8.2737 6.5465 8.33627 6.54517 8.6065C6.54783 11.0186 6.55316 13.4308 6.55316 15.8443Z"> </path> <path d="M3.65878 0.243898C5.36804 0.243898 6.58743 1.45529 6.58743 3.1406C6.58743 4.75801 5.32145 5.95742 3.60819 5.96807C3.22177 5.97614 2.83768 5.90639 2.47877 5.76299C2.11985 5.61959 1.79344 5.40546 1.51897 5.13334C1.24449 4.86123 1.02755 4.53668 0.881058 4.17902C0.734563 3.82136 0.661505 3.43788 0.666231 3.05141C0.67555 1.42601 1.9362 0.242566 3.65878 0.243898Z"> </path> </svg> <span class="usa-sr-only">NCBI on LinkedIn</span> </a> <a href="https://github.com/ncbi" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="28" height="27" viewBox="0 0 28 28" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M16.7228 20.6334C17.5057 20.5527 18.2786 20.3944 19.0301 20.1608C21.3108 19.4193 22.5822 17.8259 22.963 15.4909C23.1228 14.5112 23.1814 13.5287 22.9883 12.5437C22.8106 11.6423 22.4013 10.8028 21.8007 10.1076C21.7526 10.0605 21.7197 10 21.7064 9.934C21.6931 9.86799 21.7 9.79952 21.7262 9.73748C22.0856 8.6206 21.9711 7.51969 21.601 6.42677C21.582 6.3497 21.5345 6.2827 21.468 6.23923C21.4016 6.19577 21.3211 6.17906 21.2429 6.19248C20.7329 6.21649 20.2313 6.33051 19.7611 6.52928C19.1103 6.7908 18.4899 7.12198 17.9104 7.51703C17.84 7.56996 17.7581 7.60551 17.6713 7.62078C17.5846 7.63605 17.4954 7.6306 17.4112 7.60489C15.2596 7.05882 13.0054 7.06203 10.8554 7.61421C10.7806 7.63586 10.7018 7.63967 10.6253 7.62534C10.5487 7.611 10.4766 7.57892 10.4148 7.53167C9.64788 7.03247 8.85171 6.58918 7.96368 6.33359C7.65781 6.24338 7.34123 6.19458 7.02239 6.18849C6.94879 6.17986 6.87462 6.19893 6.81432 6.242C6.75402 6.28507 6.71191 6.34904 6.69621 6.42145C6.32342 7.51437 6.2209 8.61527 6.56307 9.73348C6.59635 9.84264 6.64694 9.93316 6.54177 10.0516C5.47666 11.2604 5.09988 12.6834 5.19574 14.2676C5.2663 15.4244 5.46201 16.5466 6.01454 17.5769C6.84399 19.1171 8.21664 19.9119 9.85158 20.3352C10.3938 20.4706 10.9444 20.5698 11.4998 20.632C11.5384 20.7492 11.4506 20.7798 11.408 20.8291C11.1734 21.1179 10.9894 21.4441 10.8634 21.7942C10.7622 22.0458 10.8315 22.4039 10.6065 22.5516C10.263 22.7766 9.83827 22.8485 9.42421 22.8871C8.17936 23.0056 7.26471 22.4877 6.6283 21.4348C6.25552 20.8184 5.76956 20.3325 5.08523 20.0663C4.76981 19.9325 4.42139 19.8967 4.08537 19.9638C3.7898 20.029 3.73788 20.1901 3.93891 20.4111C4.03639 20.5234 4.14989 20.6207 4.27575 20.6999C4.9796 21.1318 5.51717 21.7884 5.80152 22.5636C6.37002 23.9973 7.48039 24.5697 8.93825 24.6323C9.43741 24.6575 9.93768 24.615 10.4254 24.5058C10.5892 24.4672 10.6531 24.4872 10.6517 24.6762C10.6451 25.4936 10.6637 26.3123 10.6517 27.131C10.6517 27.6635 10.1684 27.9297 9.58663 27.7393C8.17396 27.2671 6.84977 26.5631 5.66838 25.656C2.59555 23.2891 0.720966 20.1861 0.217704 16.3376C-0.357453 11.9127 0.911353 8.00824 3.98551 4.73881C6.11909 2.42656 8.99932 0.939975 12.1203 0.540191C16.5351 -0.0601815 20.4347 1.14323 23.7232 4.16373C26.2449 6.47869 27.724 9.37672 28.1048 12.7726C28.5828 17.0325 27.3686 20.7945 24.4768 23.9827C22.9762 25.6323 21.0956 26.8908 18.9982 27.6488C18.8783 27.6927 18.7585 27.738 18.636 27.7726C18.0356 27.9404 17.6189 27.6395 17.6189 27.0098C17.6189 25.7452 17.6308 24.4806 17.6295 23.2159C17.6329 22.9506 17.6128 22.6856 17.5696 22.4238C17.4325 21.6664 17.3419 21.484 16.7228 20.6334Z"> </path> </svg> <span class="usa-sr-only">NCBI on GitHub</span> </a> <a href="https://ncbiinsights.ncbi.nlm.nih.gov/" class="ncbi-footer__social-icon ncbi-footer__social-icon--gray" target="_blank" rel="noreferrer noopener"> <svg width="26" height="26" viewBox="0 0 27 27" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M23.7778 26.4574C23.1354 26.3913 22.0856 26.8024 21.636 26.3087C21.212 25.8444 21.4359 24.8111 21.324 24.0347C19.9933 14.8323 14.8727 8.80132 6.09057 5.85008C4.37689 5.28406 2.58381 4.99533 0.779072 4.99481C0.202773 4.99481 -0.0229751 4.83146 0.00455514 4.21479C0.0660406 3.08627 0.0660406 1.95525 0.00455514 0.826734C-0.0413285 0.0815827 0.259669 -0.0193618 0.896534 0.00266238C6.96236 0.222904 12.3693 2.24179 16.9889 6.16209C22.9794 11.2478 26.1271 17.7688 26.4372 25.648C26.4629 26.294 26.3179 26.5271 25.6609 26.4684C25.0827 26.417 24.4991 26.4574 23.7778 26.4574Z"> </path> <path d="M14.8265 26.441C14.0924 26.441 13.2371 26.6795 12.6626 26.3786C12.0092 26.0372 12.3781 25.0644 12.246 24.378C11.1154 18.5324 6.6849 14.5497 0.74755 14.1001C0.217135 14.0615 -0.0104482 13.9422 0.0134113 13.3659C0.0519536 12.1454 0.0482829 10.9213 0.0134113 9.69524C-0.00127145 9.14464 0.196946 9.03268 0.703502 9.04736C9.21217 9.27128 16.5994 16.2511 17.2804 24.7231C17.418 26.4446 17.418 26.4446 15.6579 26.4446H14.832L14.8265 26.441Z"> </path> <path d="M3.58928 26.4555C2.64447 26.4618 1.73584 26.0925 1.06329 25.4289C0.39073 24.7653 0.00933763 23.8617 0.0030097 22.9169C-0.00331824 21.9721 0.365937 21.0635 1.02954 20.3909C1.69315 19.7184 2.59675 19.337 3.54156 19.3306C4.48637 19.3243 5.39499 19.6936 6.06755 20.3572C6.7401 21.0208 7.1215 21.9244 7.12782 22.8692C7.13415 23.814 6.7649 24.7226 6.10129 25.3952C5.43768 26.0677 4.53409 26.4491 3.58928 26.4555Z"> </path> </svg> <span class="usa-sr-only">NCBI RSS feed</span> </a> </div> </div> <div data-testid="gridContainer" class="grid-container ncbi-footer__container"> <div class="grid-row ncbi-footer__main-content-container" data-testid="grid"> <div class="ncbi-footer__column"> <p class="ncbi-footer__circled-icons-heading"> Connect with NLM </p> <div class="ncbi-footer__circled-icons-list"> <a href=https://twitter.com/nlm_nih class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="32" height="32" viewBox="0 0 40 40" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="m6.067 8 10.81 13.9L6 33.2h4.2l8.4-9.1 7.068 9.1H34L22.8 18.5 31.9 8h-3.5l-7.7 8.4L14.401 8H6.067Zm3.6 1.734h3.266l16.8 21.732H26.57L9.668 9.734Z"> </path> </svg> <span class="usa-sr-only">NLM on X (formerly known as Twitter)</span> </a> <a href=https://www.facebook.com/nationallibraryofmedicine class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="13" height="24" viewBox="0 0 13 24" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M4.11371 23.1369C4.11371 23.082 4.11371 23.0294 4.11371 22.9745V12.9411H0.817305C0.6709 12.9411 0.670898 12.9411 0.670898 12.8016C0.670898 11.564 0.670898 10.3287 0.670898 9.09341C0.670898 8.97903 0.705213 8.95158 0.815017 8.95158C1.8673 8.95158 2.91959 8.95158 3.97417 8.95158H4.12057V8.83263C4.12057 7.8055 4.12057 6.7738 4.12057 5.74897C4.1264 4.92595 4.31387 4.11437 4.66959 3.37217C5.12916 2.38246 5.94651 1.60353 6.95717 1.1921C7.64827 0.905008 8.3913 0.764035 9.13953 0.778051C10.0019 0.791777 10.8644 0.830666 11.7268 0.860404C11.8869 0.860404 12.047 0.894717 12.2072 0.90158C12.2964 0.90158 12.3261 0.940469 12.3261 1.02968C12.3261 1.5421 12.3261 2.05452 12.3261 2.56465C12.3261 3.16857 12.3261 3.7725 12.3261 4.37642C12.3261 4.48165 12.2964 4.51367 12.1912 4.51138C11.5369 4.51138 10.8804 4.51138 10.2261 4.51138C9.92772 4.51814 9.63058 4.5526 9.33855 4.61433C9.08125 4.6617 8.84537 4.78881 8.66431 4.97766C8.48326 5.16652 8.3662 5.40755 8.32972 5.66661C8.28476 5.89271 8.26027 6.1224 8.25652 6.35289C8.25652 7.19014 8.25652 8.02969 8.25652 8.86923C8.25652 8.89439 8.25652 8.91955 8.25652 8.95615H12.0219C12.1797 8.95615 12.182 8.95616 12.1614 9.10714C12.0768 9.76596 11.9876 10.4248 11.9029 11.0813C11.8312 11.6319 11.7626 12.1824 11.697 12.733C11.6719 12.9434 11.6787 12.9434 11.4683 12.9434H8.26338V22.899C8.26338 22.979 8.26338 23.0591 8.26338 23.1392L4.11371 23.1369Z"> </path> </svg> <span class="usa-sr-only">NLM on Facebook</span> </a> <a href=https://www.youtube.com/user/NLMNIH class="ncbi-footer__social-icon ncbi-footer__social-icon--circled" target="_blank" rel="noreferrer noopener"> <svg width="21" height="15" viewBox="0 0 21 15" fill="none" xmlns="http://www.w3.org/2000/svg" focusable="false" aria-hidden="true"> <path d="M19.2561 1.47914C18.9016 1.15888 18.5699 0.957569 17.2271 0.834039C15.5503 0.678484 13.2787 0.655608 11.563 0.65332H9.43556C7.71987 0.65332 5.4483 0.678484 3.77151 0.834039C2.43098 0.957569 2.097 1.15888 1.74242 1.47914C0.813665 2.32097 0.619221 4.62685 0.598633 6.89384C0.598633 7.31781 0.598633 7.74101 0.598633 8.16345C0.626084 10.4121 0.827391 12.686 1.74242 13.521C2.097 13.8412 2.4287 14.0425 3.77151 14.1661C5.4483 14.3216 7.71987 14.3445 9.43556 14.3468H11.563C13.2787 14.3468 15.5503 14.3216 17.2271 14.1661C18.5676 14.0425 18.9016 13.8412 19.2561 13.521C20.1712 12.6929 20.3725 10.451 20.3999 8.22064C20.3999 7.74025 20.3999 7.25986 20.3999 6.77946C20.3725 4.54907 20.1689 2.30724 19.2561 1.47914ZM8.55942 10.5311V4.65201L13.5601 7.50005L8.55942 10.5311Z" fill="white" /> </svg> <span class="usa-sr-only">NLM on YouTube</span> </a> </div> </div> <address class="ncbi-footer__address ncbi-footer__column"> <p> <a class="usa-link usa-link--external" href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/%4038.9959508, -77.101021,17z/data%3D!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb%3A0x19156f88b27635b8!8m2!3d38.9959508! 4d-77.0988323" rel="noopener noreferrer" target="_blank">National Library of Medicine <br/> 8600 Rockville Pike<br/> Bethesda, MD 20894</a> </p> </address> <ul class="usa-list usa-list--unstyled ncbi-footer__vertical-list ncbi-footer__column"> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/web_policies.html" class="usa-link usa-link--alt ncbi-footer__link" > Web Policies </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="usa-link usa-link--alt ncbi-footer__link" > FOIA </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > HHS Vulnerability Disclosure </a> </li> </ul> <ul class="usa-list usa-list--unstyled ncbi-footer__vertical-list ncbi-footer__column"> <li class="ncbi-footer__vertical-list-item"> <a href="https://support.nlm.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > Help </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/accessibility.html" class="usa-link usa-link--alt ncbi-footer__link" > Accessibility </a> </li> <li class="ncbi-footer__vertical-list-item"> <a href="https://www.nlm.nih.gov/careers/careers.html" class="usa-link usa-link--alt ncbi-footer__link" > Careers </a> </li> </ul> </div> <div class="grid-row grid-col-12" data-testid="grid"> <ul class="ncbi-footer__bottom-links-list"> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.nlm.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > NLM </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.nih.gov/" class="usa-link usa-link--alt ncbi-footer__link" > NIH </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.hhs.gov/" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > HHS </a> </li> <li class="ncbi-footer__bottom-list-item"> <a href="https://www.usa.gov/" class="usa-link usa-link--external usa-link--alt ncbi-footer__link" rel="noreferrer noopener" target='_blank' > USA.gov </a> </li> </ul> </div> </div> </footer> <script type="text/javascript" src="https://cdn.ncbi.nlm.nih.gov/core/pinger/pinger.js"> </script> <button class="back-to-top" data-ga-category="pagination" data-ga-action="back_to_top"> <label>Back to Top</label> <svg class="usa-icon order-0" aria-hidden="true" focusable="false" role="img"> <use xlink:href="/static/img/sprite.svg#arrow_upward"></use> </svg> </button> <script src="https://code.jquery.com/jquery-3.5.0.min.js" integrity="sha256-xNzN2a4ltkB44Mc/Jz3pT4iU1cmeR0FkXs4pru/JxaQ=" crossorigin="anonymous"> </script> <script type="text/javascript">var exports = {};</script> <script src="/static/CACHE/js/output.13b077bc3ffd.js"></script> <script type="application/javascript"> window.ncbi = window.ncbi || {}; window.ncbi.pmc = window.ncbi.pmc || {}; window.ncbi.pmc.options = { logLevel: 'INFO', staticEndpoint: '/static/', citeCookieName: 'pmc-cf', }; </script> <script type="module" crossorigin="" src="/static/assets/base-9bea7450.js"></script> <script type="module" crossorigin="" src="/static/assets/article-722d91a2.js"></script> </body> </html>

CINXE.COM

Epigallocatechin-3-Gallate (EGCG) Inhibits SARS-CoV-2 Infection in Primate Epithelial Cells: (A Short Communication) - PMC