{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:54:44Z","timestamp":1791438884761,"version":"4.3.3"},"reference-count":34,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM145351"],"award-info":[{"award-number":["R35GM145351"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI164088"],"award-info":[{"award-number":["R21AI164088"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["R21EB032983"],"award-info":[{"award-number":["R21EB032983"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["F31CA26883"],"award-info":[{"award-number":["F31CA26883"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["P30GM124169"],"award-info":[{"award-number":["P30GM124169"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["DE\u2010AC02\u201005CH11231"],"award-info":[{"award-number":["DE\u2010AC02\u201005CH11231"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP210043"],"award-info":[{"award-number":["RP210043"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    Nirmatrelvir (NMV) is a SARS\u2010CoV\u20102 antiviral component of the approved COVID\u201019 therapeutic Paxlovid. It is a reversible covalent inhibitor of SARS\u2010CoV\u20102 main protease (M\n                    <jats:sup>Pro<\/jats:sup>\n                    ) that is effluxed from human cells by P\u2010glycoprotein (P\u2010gp). To identify NMV analogs with improved potency and reduced P\u2010gp efflux, a structure\u2013activity relationship campaign was conducted. Warheads alternative to nitrile for engaging the active site cysteine were tested showing aldehyde and dichloroacetamide with better enzyme inhibition potency. Crystal structure of MPI\u2010136\u2212M\n                    <jats:sup>Pro<\/jats:sup>\n                    shows its aldehyde warhead forming a thiohemiacetal with active Cys145 of M\n                    <jats:sup>Pro<\/jats:sup>\n                    . Several S4 binders were explored revealing that an O\u2010to\u2010S shift at the\n                    <jats:italic>N<\/jats:italic>\n                    \u2010terminal amide leads to better enzyme inhibition. By exploring different combinations of S2, S3, and S4 binders, two inhibitors with better enzyme inhibition potency than NMV were found. Crystal structure of MPI\u2010148, with (\n                    <jats:italic>S<\/jats:italic>\n                    )\u20102\u2010azaspiro[4,5]decane\u20103\u2010carboxylate as an alternative S2 binder, shows extensive hydrogen\u2010bond networks for locking the inhibitor in active site, explaining high affinity of NMV analogs. Further characterization of cellular M\n                    <jats:sup>Pro<\/jats:sup>\n                    engagement and antiviral potency against SARS\u2010CoV\u20102 revealed four inhibitors with greater potency than NMV in P\u2010gp\u2010expressing cells. Studies with the P\u2010gp inhibitor CP\u2010100356 showed that these compounds were less sensitive to P\u2010gp inhibition than NMV, consistent with reduced P\u2010gp\u2010mediated efflux.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70424","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T01:26:11Z","timestamp":1786497971000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploration of Nirmatrelvir Derivatives as Optimized SARS\u2010CoV\u20102 Antivirals"],"prefix":"10.1002","volume":"21","author":[{"given":"Yugendar R.","family":"Alugubelli","sequence":"first","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-5674","authenticated-orcid":false,"given":"Veerabhadra R.","family":"Vulupala","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai S.","family":"Yang","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaustav","family":"Khatua","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren R.","family":"Blankenship","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-1813","authenticated-orcid":false,"given":"Demonta","family":"Coleman","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Guo","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0790-1595","authenticated-orcid":false,"given":"Zhi Zachery","family":"Geng","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Chuan D.","family":"Cho","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banumathi","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Molecular Biophysics and Integrated Bioimaging Berkeley Center for Structural Biology Laurence Berkeley National Laboratory  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1240-8954","authenticated-orcid":false,"given":"Benjamin W.","family":"Neuman","sequence":"additional","affiliation":[{"name":"Department of Biology College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"},{"name":"Texas A&amp;M Global Health Research Complex Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Molecular Pathogenesis and Immunology College of Medicine  Bryan Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6260-9290","authenticated-orcid":false,"given":"Shiqing","family":"Xu","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Pharmaceutical Sciences Irma Lerma Rangel College of Pharmacy Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7078-6534","authenticated-orcid":false,"given":"Wenshe Ray","family":"Liu","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Drug Discovery Center Department of Chemistry College of Arts and Sciences Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Pharmaceutical Sciences Irma Lerma Rangel College of Pharmacy Texas A&amp;M University  College Station Texas USA"},{"name":"Institute of Biosciences and Technology Department of Translational Medical Sciences School of Medicine Texas A&amp;M University  Houston Texas USA"},{"name":"Department of Biochemistry and Biophysics College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Cell Biology and Genetics College of Medicine Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.011"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7"},{"key":"e_1_2_8_4_1","unstructured":"JHU Johns Hopkins Coronavirus Resource Center. COVID\u201019 dashboard https:\/\/coronavirus.jhu.edu\/map.html 2021."},{"key":"e_1_2_8_5_1","unstructured":"WHO Middle East respiratory syndrome coronavirus (MERS\u2010CoV) https:\/\/www.who.int\/emergencies\/mers\u2010cov\/en\/ 2021."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202000047"},{"key":"e_1_2_8_8_1","first-page":"m3862","article-title":"Virology, Transmission, and Pathogenesis of SARS\u2010CoV\u20102","volume":"371","author":"Cevik M.","year":"2020","journal-title":"BMJ (Clinical Research Ed.)"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(67)80055-X"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00117"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42102-y"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00539-24"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102359"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101972"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2022.105252"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00640-y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128629"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04856-1"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1MD00247C"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08487-w"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18233-x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0356-z"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0MD00367K"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.4c00146"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114596"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01825"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114570"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b11027"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01627"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2017.10.002"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.105874"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000924"},{"key":"e_1_2_8_34_1","first-page":"469","article-title":"Analysis of Cell Viability by the MTT Assay","volume":"2018","author":"Kumar P.","year":"2018","journal-title":"Cold Spring Harbor Protocols"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.1c00910"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70424","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70424","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70424","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:35:14Z","timestamp":1791437714000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":34,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,8,14]]}},"alternative-id":["10.1002\/cmdc.70424"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70424","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"assertion":[{"value":"2026-02-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70424"}}