Structure-based design of bitopic ligands for the µ-opioid receptor

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Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment—one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology. 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Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment—one&nbsp;(C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. 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class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Abdelfattah-Faouzi-Aff1" data-author-popup="auth-Abdelfattah-Faouzi-Aff1" data-author-search="Faouzi, Abdelfattah">Abdelfattah Faouzi</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-9059-4791"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-9059-4791</a></span><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Haoqing-Wang-Aff2" data-author-popup="auth-Haoqing-Wang-Aff2" data-author-search="Wang, Haoqing">Haoqing Wang</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Saheem_A_-Zaidi-Aff3" data-author-popup="auth-Saheem_A_-Zaidi-Aff3" data-author-search="Zaidi, Saheem A.">Saheem A. Zaidi</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jeffrey_F_-DiBerto-Aff4" data-author-popup="auth-Jeffrey_F_-DiBerto-Aff4" data-author-search="DiBerto, Jeffrey F.">Jeffrey F. DiBerto</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-8227-2071"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-8227-2071</a></span><sup class="u-js-hide"><a href="#Aff4">4</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Tao-Che-Aff1-Aff4" data-author-popup="auth-Tao-Che-Aff1-Aff4" data-author-search="Che, Tao">Tao Che</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-1620-3027"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-1620-3027</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff4">4</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Qianhui-Qu-Aff2-Aff5" data-author-popup="auth-Qianhui-Qu-Aff2-Aff5" data-author-search="Qu, Qianhui">Qianhui Qu</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-5753-2599"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-5753-2599</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff5">5</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael_J_-Robertson-Aff2-Aff5" data-author-popup="auth-Michael_J_-Robertson-Aff2-Aff5" data-author-search="Robertson, Michael J.">Michael J. Robertson</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0003-2610-680X"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0003-2610-680X</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Manish_K_-Madasu-Aff1" data-author-popup="auth-Manish_K_-Madasu-Aff1" data-author-search="Madasu, Manish K.">Manish K. Madasu</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Amal-El_Daibani-Aff1" data-author-popup="auth-Amal-El_Daibani-Aff1" data-author-search="El Daibani, Amal">Amal El Daibani</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Balazs_R_-Varga-Aff1" data-author-popup="auth-Balazs_R_-Varga-Aff1" data-author-search="Varga, Balazs R.">Balazs R. Varga</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Tiffany-Zhang-Aff6" data-author-popup="auth-Tiffany-Zhang-Aff6" data-author-search="Zhang, Tiffany">Tiffany Zhang</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Claudia-Ruiz-Aff7" data-author-popup="auth-Claudia-Ruiz-Aff7" data-author-search="Ruiz, Claudia">Claudia Ruiz</a><sup class="u-js-hide"><a href="#Aff7">7</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Shan-Liu-Aff8" data-author-popup="auth-Shan-Liu-Aff8" data-author-search="Liu, Shan">Shan Liu</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jin-Xu-Aff8" data-author-popup="auth-Jin-Xu-Aff8" data-author-search="Xu, Jin">Jin Xu</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kevin-Appourchaux-Aff1" data-author-popup="auth-Kevin-Appourchaux-Aff1" data-author-search="Appourchaux, Kevin">Kevin Appourchaux</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Samuel_T_-Slocum-Aff4" data-author-popup="auth-Samuel_T_-Slocum-Aff4" data-author-search="Slocum, Samuel T.">Samuel T. Slocum</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Shainnel_O_-Eans-Aff9" data-author-popup="auth-Shainnel_O_-Eans-Aff9" data-author-search="Eans, Shainnel O.">Shainnel O. Eans</a><sup class="u-js-hide"><a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael_D_-Cameron-Aff7" data-author-popup="auth-Michael_D_-Cameron-Aff7" data-author-search="Cameron, Michael D.">Michael D. Cameron</a><sup class="u-js-hide"><a href="#Aff7">7</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ream-Al_Hasani-Aff1" data-author-popup="auth-Ream-Al_Hasani-Aff1" data-author-search="Al-Hasani, Ream">Ream Al-Hasani</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-8781-6234"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-8781-6234</a></span><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ying_Xian-Pan-Aff6-Aff8" data-author-popup="auth-Ying_Xian-Pan-Aff6-Aff8" data-author-search="Pan, Ying Xian">Ying Xian Pan</a><sup class="u-js-hide"><a href="#Aff6">6</a>,<a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Bryan_L_-Roth-Aff4" data-author-popup="auth-Bryan_L_-Roth-Aff4" data-author-search="Roth, Bryan L.">Bryan L. Roth</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-0561-6520"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-0561-6520</a></span><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jay_P_-McLaughlin-Aff9" data-author-popup="auth-Jay_P_-McLaughlin-Aff9" data-author-search="McLaughlin, Jay P.">Jay P. McLaughlin</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-9851-9342"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-9851-9342</a></span><sup class="u-js-hide"><a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Georgios-Skiniotis-Aff2-Aff5" data-author-popup="auth-Georgios-Skiniotis-Aff2-Aff5" data-author-search="Skiniotis, Georgios" data-corresp-id="c1">Georgios Skiniotis<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0003-0238-7846"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0003-0238-7846</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Vsevolod-Katritch-Aff3" data-author-popup="auth-Vsevolod-Katritch-Aff3" data-author-search="Katritch, Vsevolod" data-corresp-id="c2">Vsevolod Katritch<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0003-3883-4505"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0003-3883-4505</a></span><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Brian_K_-Kobilka-Aff2" data-author-popup="auth-Brian_K_-Kobilka-Aff2" data-author-search="Kobilka, Brian K." data-corresp-id="c3">Brian K. Kobilka<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-5958-3990"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-5958-3990</a></span><sup class="u-js-hide"><a href="#Aff2">2</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 26 authors for this article" title="Show all 26 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Susruta-Majumdar-Aff1" data-author-popup="auth-Susruta-Majumdar-Aff1" data-author-search="Majumdar, Susruta" data-corresp-id="c4">Susruta Majumdar<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-2931-3823"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-2931-3823</a></span><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 613</b>, <span class="u-visually-hidden">pages </span>767–774 (<span data-test="article-publication-year">2023</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">21k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">55 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">215 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/s41586-022-05588-y/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/medicinal-chemistry" data-track="click" data-track-action="view subject" data-track-label="link">Medicinal chemistry</a></li><li class="c-article-subject-list__subject"><a href="/subjects/pharmacology" data-track="click" data-track-action="view subject" data-track-label="link">Pharmacology</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="DeWeerdt, S. Tracing the US opioid crisis to its roots. Nature 573, S10–S12 (2019)." href="/articles/s41586-022-05588-y#ref-CR1" id="ref-link-section-d92993173e784">1</a></sup>. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Zarzycka, B., Zaidi, S. A., Roth, B. L. & Katritch, V. Harnessing ion-binding sites for GPCR pharmacology. Pharmacol. Rev. 71, 571–595 (2019)." href="/articles/s41586-022-05588-y#ref-CR2" id="ref-link-section-d92993173e788">2</a></sup> found in µOR<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Huang, W. et al. Structural insights into μ-opioid receptor activation. Nature 524, 315–321 (2015)." href="/articles/s41586-022-05588-y#ref-CR3" id="ref-link-section-d92993173e792">3</a></sup> and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp<sup>2.50</sup> residue in the Na<sup>+</sup> site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G<sub>i</sub> subtypes and show strongly reduced arrestin recruitment—one (C6 guano) also shows the lowest G<sub>z</sub> efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G<sub>i</sub>, G<sub>o</sub> and G<sub>z</sub> subtypes and arrestins, thus modulating their in vivo pharmacology.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41586-022-05588-y" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or 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class="u-display-none"> <div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1: Targeting the Na<sup>+</sup> site with fentanyl-based bitopic ligands and characterization of lead compounds in binding, G-protein and arrestin signalling assays.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig1_HTML.png?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig1_HTML.png" alt="" loading="lazy" width="312" height="136"></picture></div></div></figure></div><div class="c-article-section__figure 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data-test="figure-caption-text">Fig. 3: Profiling of C5 guano, C6 guano and µOR using TRUPATH Gαβγ biosensors and β-arrestin-1 and β-arrestin-2 efficacy.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig3_HTML.png?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig3_HTML.png" alt="" loading="lazy" width="312" height="192"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4: C6 guano exhibits µOR-mediated antinociception without CPP, CPA or 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js-section-title js-c-reading-companion-sections-item" id="data-availability">Data availability</h2><div class="c-article-section__content" id="data-availability-content"> <p>The cryo-EM maps and corresponding coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes <a href="http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-26314">EMD-26314</a> (C5 guano–μOR–G<sub>i</sub>–scFv16) and <a href="http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-26313">EMD-26313</a> (C6 guano–μOR–G<sub>i</sub>) and the Protein Data Bank (PDB) under accession codes <a href="https://doi.org/10.2210/pdb7U2L/pdb">7U2L</a> (C5 guano–μOR–G<sub>i</sub>–scFv16) and <a href="http://doi.org/10.2210/pdb7U2K/pdb">7U2K</a> (C6 guano–μOR–G<sub>i</sub>). The authors declare that all the data supporting the findings of this study are available within the article, extended data and supplementary information files. All compounds can be made available on reasonable requests from the authors. <a data-track="click" data-track-label="link" data-track-action="section anchor" href="/articles/s41586-022-05588-y#Sec14">Source data</a> are provided with this paper.</p> </div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">DeWeerdt, S. 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B.K.K. and G.S. are additionally supported by the Mathers Foundation and R.A.-H. is supported through the Brain and Behavior Research Foundation. The State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development provides funding to J.P.M. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to MSKCC. Cryo-EM data collection was performed at the Stanford-SLAC Cryo-EM Facilities, supported by Stanford University, SLAC and the National Institutes of Health S10 Instrumentation Programs. The authors thank E. Montabana and C. Zhang for their support with cryo-EM data collection; and Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. Cryo-EM data processing for this project was performed on the Sherlock cluster. The authors acknowledge the Center for Advanced Research Computing (CARC) at the University of Southern California for providing computing resources that have contributed to the research results reported in this study. Receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP), contract no. HHSN-271-2018-00023-C. B.L.R. is director of NIMH PDSP at the University of North Carolina at Chapel Hill and J.D. is project officer of NIMH PDSP at NIMH, Bethesda.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="na1"><p>These authors contributed equally: Abdelfattah Faouzi, Haoqing Wang, Saheem A. Zaidi, Jeffrey F. DiBerto, Tao Che, Qianhui Qu</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St Louis, MO, USA</p><p class="c-article-author-affiliation__authors-list">Abdelfattah Faouzi, Tao Che, Manish K. Madasu, Amal El Daibani, Balazs R. Varga, Kevin Appourchaux, Ream Al-Hasani & Susruta Majumdar</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Haoqing Wang, Qianhui Qu, Michael J. Robertson, Georgios Skiniotis & Brian K. Kobilka</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Quantitative and Computational Biology, Department of Chemistry, Bridge Institute and Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA</p><p class="c-article-author-affiliation__authors-list">Saheem A. Zaidi & Vsevolod Katritch</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA</p><p class="c-article-author-affiliation__authors-list">Jeffrey F. DiBerto, Tao Che, Samuel T. Slocum & Bryan L. Roth</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Qianhui Qu, Michael J. Robertson & Georgios Skiniotis</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA</p><p class="c-article-author-affiliation__authors-list">Tiffany Zhang & Ying Xian Pan</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Chemistry, Scripps Research, Jupiter, FL, USA</p><p class="c-article-author-affiliation__authors-list">Claudia Ruiz & Michael D. Cameron</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, USA</p><p class="c-article-author-affiliation__authors-list">Shan Liu, Jin Xu & Ying Xian Pan</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA</p><p class="c-article-author-affiliation__authors-list">Shainnel O. Eans & Jay P. McLaughlin</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Abdelfattah-Faouzi-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Abdelfattah Faouzi</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Abdelfattah%20Faouzi" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Abdelfattah%20Faouzi" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Abdelfattah%20Faouzi%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Haoqing-Wang-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Haoqing Wang</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Haoqing%20Wang" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Haoqing%20Wang" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Haoqing%20Wang%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Saheem_A_-Zaidi-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Saheem A. 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A.F. and B.R.V. synthesized the compounds, aided in their characterization under the supervision of S.M. H.W. prepared the μOR–G<sub>i</sub> complex, obtained and processed cryo-EM data, and refined the structure from cryo-EM density maps under the supervision of B.K.K. and G.S. S.A.Z. performed the docking, ligand design, and molecular dynamics simulations under the supervision of V.K. Q.Q. and M.J.R obtained and processed cryo-EM data under the supervision of G.S. S.T.S. and J.F.D. performed the profiling studies under the supervision of B.L.R. A.E.D. performed the profiling studies under the supervision of T.C. K.A. carried out TRUPATH and pharmacokinetics assays under the supervision of S.M. T.Z. carried out binding assays under the supervision of Y.X.P. S.L. and J.X. performed the antinociception assay with ICV administration under the supervision of Y.X.P. C.R. carried out mouse brain stability assays under the supervision of M.D.C. S.O.E. and M.K.M. carried out behavioural assays under the supervision of J.P.M. and R.A.H., respectively. A.F., H.W., S.A.Z., J.F.D, J.P.M., V.K., G.S., B.K.K. and S.M. wrote the paper with contributions from the other authors.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:yiorgo@stanford.edu">Georgios Skiniotis</a>, <a id="corresp-c2" href="mailto:Katritch@usc.edu">Vsevolod Katritch</a>, <a id="corresp-c3" href="mailto:kobilka@stanford.edu">Brian K. Kobilka</a> or <a id="corresp-c4" href="mailto:susrutam@email.wustl.edu">Susruta Majumdar</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading" id="FPar2">Competing interests</h3> <p>S.M. and Y.X.P. are founders of Sparian Biosciences. B.K.K. is a founder of and consultant for ConfometRx. G.S. is a cofounder of Deep Apple. All other authors declare no competing interests.</p> </div></div></section><section data-title="Peer review"><div class="c-article-section" id="peer-review-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="peer-review">Peer review</h2><div class="c-article-section__content" id="peer-review-content"> <h3 class="c-article__sub-heading" id="FPar1">Peer review information</h3> <p><i>Nature</i> thanks the anonymous reviewer(s) for their contribution to the peer review of this work.</p> </div></div></section><section data-title="Additional information"><div class="c-article-section" id="additional-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="additional-information">Additional information</h2><div class="c-article-section__content" id="additional-information-content"><p><b>Publisher’s note</b> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></div></div></section><section data-title="Extended data figures and tables"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">Extended data figures and tables</h2><div class="c-article-section__content" id="Sec12-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig5"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 1 docking of a fentanyl based b" href="/articles/s41586-022-05588-y/figures/5" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig5_ESM.jpg">Extended Data Fig. 1 Docking of a fentanyl based bitopic targeting the Na<sup>+</sup> binding site.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Molecular docking of a fentanyl based bitopic ligand shows that the functional head group can target the Na<sup>+</sup> pocket.</p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig6"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 2 cryo-em data processing work-" href="/articles/s41586-022-05588-y/figures/6" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig6_ESM.jpg">Extended Data Fig. 2 Cryo-EM data processing work-flows.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Representative micrographs, 2D classes, 3D classes and data processing procedures for (A) C5-guano and (B) C6-guano bound µOR–G<sub>i</sub>-scFv16 complex.</p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig7"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 3 global and local resolutions " href="/articles/s41586-022-05588-y/figures/7" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig7_ESM.jpg">Extended Data Fig. 3 Global and local resolutions for cryo-EM maps.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>(A) Gold-standard FSC curves for C5-guano and C6-guano bound μOR–G<sub>i</sub> structures. Overall resolution is 3.2 Å for C5-guano bound μOR–G<sub>i</sub>-scFv16 and 3.3 Å for C6-guano bound μOR–G<sub>i</sub> using the gold Standard FSC = 0.143 criterion. (B) Local resolution map of C5 guano and C6 guano bound μOR–G<sub>i</sub> structures. (C) Data collection, refinement, and model statistic of two structures. Extended Data Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-022-05588-y#Tab2">2</a>. Cryo-EM data collection, refinement and validation statistics.</p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig8"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 4 comparison of bitopic structu" href="/articles/s41586-022-05588-y/figures/8" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig8_ESM.jpg">Extended Data Fig. 4 Comparison of bitopic structures to BU72 structure.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>A, C, Side chains of μOR orthosteric pocket residues are shown for the C5-guano (A) and C6-guano (C) bound μOR–G<sub>i</sub> complex (green) in comparison with the BU72 bound μOR (PDB code 5C1M; pink). The orthosteric pocket residues of μOR in complex with bitopic ligands and BU72 show nearly identical conformations. B, D, Side chains of μOR site-2 and Na<sup>+</sup> site residues are shown for the C5 guano (B) and C6 guano (D) bound μOR–G<sub>i</sub> complex (green) in comparison with the BU72 bound μOR (PDB code 5C1M; pink). The site-2 and Na<sup>+</sup> site residues of μOR in complex with bitopic ligands and BU72 show nearly identical conformations.</p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig9"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 5 analysis of dynamics of direc" href="/articles/s41586-022-05588-y/figures/9" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig9_ESM.jpg">Extended Data Fig. 5 Analysis of dynamics of direct and water mediated interactions of bitopic ligands.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>A) Overlay of three examples of C5 guano conformations bound to active state MOR (pink cartoon/sticks) during MD simulations (B) Detailed view of the interactions between guano moiety of C5 guano (orange sticks) and D114<sup>2.50</sup> mediated by two water molecule (C) Direct salt bridge interactions between C5 guano (light green sticks) and D116<sup>2.50</sup> supplemented by an additional water-mediated hydrogen bond. (D) direct salt bridge interactions between C5 guano (cyan sticks) and D114<sup>2.50</sup> (E) Probability densities of distances between guano nitrogen atoms and D114<sup>2.50</sup> carboxylate oxygens. Each chart plots probability density for frames with two bridging waters (orange), one bridging water (green), and no bridging waters (cyan). (F) Categorization and relative proportion of D2.50 and D3.32 mediated interactions in 10 independent C5 guano-μOR MD trajectories for 1 μs each. Among the cumulative frames from the 10 μs MD runs, close to 1/3<sup>rd</sup> of the frames-maintained guano-D2.50 interactions exclusively through water-mediated hydrogen bonds, while ~57% frames formed direct salt- bridges with or without supplementary water mediated interactions. Therefore, close to 90% of the frames maintained D2.50-guano interactions. The piperidine-D3.32 interactions were observed to be even more stable, with over 96% of the frames indicating direct salt bridge or water-mediated hydrogen bonds. (G) Categorization and relative proportion of D2.50 and D3.32 mediated interactions in 5 independent C6-μOR trajectories for 1 μs each. Overall, the number of direct interactions with D2.50 increased from 57% to 85% (compared to C5), perhaps resulting from the increase in linker length by a carbon atom that decreases the overall distances to D2.50 residue.</p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig10"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="extended data fig. 6 profiling of chemically and p" href="/articles/s41586-022-05588-y/figures/10" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_Fig10_ESM.jpg">Extended Data Fig. 6 Profiling of chemically and pharmacologically distinct μOR agonists using TRUPATH, arrestin signaling.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>A) Peptides: Endomorphin-1, Leu-enkephalin, Met-enkephalin, Beta- endorphin and Dynorphin A (1-17). Dynorphin A (1-17) showed reduced arrestin recruitment while other peptides retained robust arrestin recruitment among peptides tested. B) Opioid biased agonists and partials: PZM21, TRV130, Gα- subtype selectivity and arrestin recruitment on μOR. PZM21, 7-OH and TRV130 showed <50% efficacy for arrestin1/2. Highest efficacy for all three biased agonists was seen at the G<sub>z</sub>-subtype. μOR partial agonist pentazocine was a full agonist at the G<sub>z</sub> subtype. C) Oxycodone and Carfentanil, Gα- subtype selectivity and arrestin recruitment on μOR. Carfentanil showed near maximal efficacy at all Gα-subtypes and arrestin1/2. Oxycodone was a full agonist at G<sub>z</sub> and showed >50% efficacy at β-arrestin2. D) Fentanyl guano bitopics show differential G-protein and arrestin efficacy with increased chain length.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-022-05588-y#MOESM3">Source Data</a></p></div></div><div class="c-article-supplementary__item" data-test="supp-item"><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Extended Data Table 1 Summary of binding affinities, cAMP and arrestin recruitment values of fentanyl amino and guano bitopics on μOR</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41586-022-05588-y/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div><div class="c-article-supplementary__item" data-test="supp-item"><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-2"><figure><figcaption class="c-article-table__figcaption"><b id="Tab2" data-test="table-caption">Extended Data Table 2 Cryo-EM data collection, refinement and validation statistics</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41586-022-05588-y/tables/2" aria-label="Full size table 2"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div><div class="c-article-supplementary__item" data-test="supp-item"><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-3"><figure><figcaption class="c-article-table__figcaption"><b id="Tab3" data-test="table-caption">Extended Data Table 3 Potency table for drugs profiled in Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-022-05588-y#Fig10">6</a></b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41586-022-05588-y/tables/3" aria-label="Full size table 3"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div><div class="c-article-supplementary__item" data-test="supp-item"><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-4"><figure><figcaption class="c-article-table__figcaption"><b id="Tab4" data-test="table-caption">Extended Data Table 4 Efficacy table for drugs profiled in Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-022-05588-y#Fig10">6</a></b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41586-022-05588-y/tables/4" aria-label="Full size table 4"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec13-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec13">Supplementary information</h2><div class="c-article-section__content" id="Sec13-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary information" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_MOESM1_ESM.pdf" data-supp-info-image="">Supplementary Information</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>This file contains the following six sections. Section 1: Material and methods; Section 2: Procedure and synthetic schemes for fentanyl bitopics; Section 3: Spectral data of fentanyl bitopics; Section 4: Additional tables and figures; Section 5: Ethics declaration; and Section 6: References.</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM2"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="reporting summary" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_MOESM2_ESM.pdf" data-supp-info-image="">Reporting Summary</a></h3></div></div></div></div></section><section data-title="Source data"><div class="c-article-section" id="Sec14-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec14">Source data</h2><div class="c-article-section__content" id="Sec14-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM3"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="source data figs. 1, 3 and 4, extended data fig. 6" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-022-05588-y/MediaObjects/41586_2022_5588_MOESM3_ESM.xlsx" data-supp-info-image="">Source Data Figs. 1, 3 and 4, Extended Data Fig. 6 and Extended Data Tables 1, 2 and 3</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"><p>Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</p><p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=Structure-based%20design%20of%20bitopic%20ligands%20for%20the%20%C2%B5-opioid%20receptor&author=Abdelfattah%20Faouzi%20et%20al&contentID=10.1038%2Fs41586-022-05588-y&copyright=The%20Author%28s%29%2C%20under%20exclusive%20licence%20to%20Springer%20Nature%20Limited&publication=0028-0836&publicationDate=2022-11-30&publisherName=SpringerNature&orderBeanReset=true">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="article-info">About this article</h2><div class="c-article-section__content" id="article-info-content"><div class="c-bibliographic-information"><div class="u-hide-print c-bibliographic-information__column c-bibliographic-information__column--border"><a data-crossmark="10.1038/s41586-022-05588-y" target="_blank" rel="noopener" href="https://crossmark.crossref.org/dialog/?doi=10.1038/s41586-022-05588-y" data-track="click" data-track-action="Click Crossmark" data-track-label="link" data-test="crossmark"><img loading="lazy" width="57" height="81" alt="Check for updates. 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Faouzi, A., Wang, H., Zaidi, S.A. <i>et al.</i> Structure-based design of bitopic ligands for the µ-opioid receptor. <i>Nature</i> <b>613</b>, 767–774 (2023). https://doi.org/10.1038/s41586-022-05588-y</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41586-022-05588-y?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2022-02-14">14 February 2022</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2022-11-22">22 November 2022</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2022-11-30">30 November 2022</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Issue Date<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2023-01-26">26 January 2023</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span 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