{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T07:36:23Z","timestamp":1782545783041,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2021,1,19]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inhibition of coronavirus (CoV)\u2010encoded papain\u2010like cysteine proteases (PL<jats:sup>pro<\/jats:sup>) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure\u2010activity relationships (SAR) of the noncovalent active\u2010site directed inhibitor (<jats:italic>R<\/jats:italic>)\u20105\u2010amino\u20102\u2010methyl\u2010N\u2010(1\u2010(naphthalen\u20101\u2010yl)ethyl) benzamide (<jats:bold>2\u2009b<\/jats:bold>), which is known to bind into the S3 and S4 pockets of the SARS\u2010CoV PL<jats:sup>pro<\/jats:sup>. Moreover, we report the discovery of isoindolines as a new class of potent PL<jats:sup>pro<\/jats:sup> inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS\u2010CoV\u20102 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS\u2010CoV PL<jats:sup>pro<\/jats:sup> are valuable starting points for the development of new pan\u2010coronaviral inhibitors.<\/jats:p>","DOI":"10.1002\/cmdc.202000548","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T18:11:27Z","timestamp":1600279887000},"page":"340-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Structure\u2010Activity Relationships of Benzamides and Isoindolines Designed as SARS\u2010CoV Protease Inhibitors Effective against SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"16","author":[{"given":"Armin","family":"Welker","sequence":"first","affiliation":[{"name":"Institute for Pharmacy and Food Chemistry Justus Maximilians University W\u00fcrzburg  Am Hubland 97074 W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kersten","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology Justus Liebig University Giessen  Schubertstrasse 81 35392 Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramakanth","family":"Madhugiri","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology Justus Liebig University Giessen  Schubertstrasse 81 35392 Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-9234","authenticated-orcid":false,"given":"Robert","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Maus","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Ziebuhr","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology Justus Liebig University Giessen  Schubertstrasse 81 35392 Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Sotriffer","sequence":"additional","affiliation":[{"name":"Institute for Pharmacy and Food Chemistry Justus Maximilians University W\u00fcrzburg  Am Hubland 97074 W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Schirmeister","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Biomedical Sciences Johannes Gutenberg University Mainz  Staudingerweg 5 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,16]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1056\/NEJMoa030747","volume":"348","author":"Drosten C.","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/S0140-6736(03)13077-2","volume":"361","author":"Peiris J. S. M.","year":"2003","journal-title":"Lancet"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1056\/NEJMoa030781","volume":"348","author":"Ksiazek T. G.","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1056\/NEJMoa1211721","volume":"367","author":"Zaki A. M.","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/S0140-6736(19)33221-0","volume":"395","author":"Memish Z. A.","year":"2020","journal-title":"Lancet"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","volume":"579","author":"Zhou P.","year":"2020","journal-title":"Nature"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","volume":"382","author":"Zhu N.","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_7_8_1","first-page":"5","author":"Gorbalenya A.","year":"2020","journal-title":"Nat. Microbiol."},{"key":"e_1_2_7_9_1","first-page":"184","volume":"64","author":"O\u2032Keefe L. C.","year":"2016","journal-title":"Work.\u00a0Heal.\u00a0Saf."},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nrd.2015.37","volume":"15","author":"Zumla A.","year":"2016","journal-title":"Nat. Rev. Drug Discovery"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0065-3527(06)66005-3","volume":"65","author":"Masters P. S.","year":"2006","journal-title":"Adv. Virus Res."},{"key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1099\/vir.0.19424-0","volume":"84","author":"Thiel V.","year":"2003","journal-title":"J. Gen. Virol."},{"key":"e_1_2_7_13_1","first-page":"96","author":"Snijder E. J.","year":"2016","journal-title":"Adv. Virus Res."},{"key":"e_1_2_7_14_1","first-page":"10","volume":"15","author":"Freitas B. T.","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"e_1_2_7_15_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","volume":"368","author":"Zhang L.","year":"2020","journal-title":"Science."},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"15189","DOI":"10.1128\/JVI.79.24.15189-15198.2005","volume":"79","author":"Barretto N.","year":"2005","journal-title":"J. Virol."},{"key":"e_1_2_7_17_1","author":"Stoermer M. J.","year":"2019","journal-title":"ChemRxiv"},{"key":"e_1_2_7_18_1","doi-asserted-by":"crossref","unstructured":"R. Arya A. Das V. Prashar M. Kumar Chemrxiv.Org2020 DOI: 10.26434\/chemrxiv.11860011 https:\/\/chemrxiv.org\/articles\/Potential_Inhibitors_Against_Papain-like_Protease_of\u2002Novel_Coronavirus_COVID-19_from_FDA_Approved_Drugs\/11860011 1\u20138.","DOI":"10.26434\/chemrxiv.11860011.v1"},{"key":"e_1_2_7_19_1","author":"Rut W.","year":"2020","journal-title":"bioRxiv Prepr. Serv. Biol."},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"16119","DOI":"10.1073\/pnas.0805240105","volume":"105","author":"Ratia K.","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_2_7_21_1","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1021\/jm401712t","volume":"57","author":"B\u00e1ez-Santos Y. M.","year":"2014","journal-title":"J. Med. Chem."},{"key":"e_1_2_7_22_1","doi-asserted-by":"crossref","first-page":"4968","DOI":"10.1021\/jm1004489","volume":"53","author":"Ghosh A. K.","year":"2010","journal-title":"J. Med. Chem."},{"key":"e_1_2_7_23_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.antiviral.2014.12.015","volume":"115","author":"B\u00e1ez-Santos Y. M.","year":"2015","journal-title":"Antiviral Res."},{"key":"e_1_2_7_24_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1371\/journal.ppat.1004113","volume":"10","author":"Ratia K.","year":"2014","journal-title":"PLoS Pathog."},{"key":"e_1_2_7_25_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.antiviral.2017.12.010","volume":"150","author":"M\u00fcller C.","year":"2018","journal-title":"Antiviral Res."},{"key":"e_1_2_7_26_1","doi-asserted-by":"crossref","unstructured":"A. Osipiuk J. Tesar C. Jedrzejczak R. Endres M. Welk L. Babnigg G. Kim Y. Michalska K. Joachimiak \u201cRCSB PDB - 6WRH: The crystal structure of Papain-Like Protease of SARS CoV-2 C111S mutant \u201d2020.","DOI":"10.2210\/pdb6wrh\/pdb"},{"key":"e_1_2_7_27_1","doi-asserted-by":"crossref","unstructured":"A. Osipiuk J. Jedrzejczak R. Tesar C. Endres M. Stols L. Babnigg G. Kim Y. Michalska K. Joachimiak \u201cRCSB PDB - 6W9C: The crystal structure of papain-like protease of SARS CoV-2 \u201d DOI: https:\/\/doi.org\/10.2210\/pdb6W9C\/pdb.","DOI":"10.2210\/pdb6w9c\/pdb"},{"key":"e_1_2_7_28_1","unstructured":"LeadIT version 2.3.2; BioSolveIT GmbH Sankt Augustin Germany 2017 www.biosolveit.de\/LeadIT."},{"key":"e_1_2_7_29_1","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1021\/jm300687e","volume":"55","author":"Mysinger M. M.","year":"2012","journal-title":"J. Med. Chem."},{"key":"e_1_2_7_30_1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/(SICI)1096-987X(199604)17:5\/6<490::AID-JCC1>3.0.CO;2-P","volume":"17","author":"Halgren T. A","year":"1996","journal-title":"J. Comput. Chem."},{"key":"e_1_2_7_31_1","unstructured":"Molecular Operationg Environment (MOE) Chemical Computing Group Inc. 2010."},{"key":"e_1_2_7_32_1","unstructured":"Schr\u00f6dinger. The PyMOL Molecular Graphics System Version 2.0."},{"key":"e_1_2_7_33_1","unstructured":"SeeSAR version 10.0; BioSolveIT GmbH Sankt Augustin Germany 2020 www.biosolveit.de\/SeeSAR."}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202000548","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202000548","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202000548","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T09:42:10Z","timestamp":1760262130000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202000548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,16]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,1,19]]}},"alternative-id":["10.1002\/cmdc.202000548"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202000548","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,16]]},"assertion":[{"value":"2020-07-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}