{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T14:58:56Z","timestamp":1780066736121,"version":"3.54.0"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The COVID\u201019 pandemic underscored the urgent need for effective antiviral agents, particularly against coronaviruses, which pose a continuing threat of future outbreaks. Targeting the main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ), a key enzyme in viral replication, represents a promising therapeutic strategy. This study investigates structural modifications to known M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors, focusing on substitutions at the P2 position to explore alterations in both inhibitory potency and metabolic stability. Computational modeling and biochemical assays revealed that incorporating large, hydrophobic, and \u03c0\u2010rich groups, such as the 4\u2010phenylproline, significantly enhances binding affinity. Additionally, we evaluated warheads that have not yet been explored in the context of SARS\u2010CoV\u20102 M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibition. Among these, fluoro\u2010vinylsulfone and nitrile groups demonstrated superior inhibitory activity. A fragment\u2010merging strategy combining an optimized P2 substituent with the nitrile warhead yielded a hybrid molecule with binding affinity comparable to nirmatrelvir. However, other analogs incorporating individual warhead optimizations displayed similar potency. These findings generate valuable insights into the design of robust M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors and support their potential development as broad\u2010spectrum antiviral agents.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70158","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T11:48:28Z","timestamp":1764416908000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring Nirmatrelvir Derivatives Through P2 Substituent Modifications and Warhead Innovations Targeting the Main Protease of SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5030-9431","authenticated-orcid":false,"given":"Felipe Cardoso Prado","family":"Martins","sequence":"first","affiliation":[{"name":"Medicinal and Biological Chemistry Group, S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo S\u00e3o Carlos S\u00e3o Paulo Brazil"},{"name":"Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8215-6302","authenticated-orcid":false,"given":"Johannes","family":"Lang","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda dos Reis","family":"Rocho","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group, S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vin\u00edcius","family":"Bonatto","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group, S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jer\u00f4nimo","family":"Lameira","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group, S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Klein","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Alberto","family":"Montanari","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group, S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"Worldometer. COVID\u201019 Coronavirus Pandemic.Worldofmeters.info accessed March 2025 https:\/\/www.worldometers.info\/coronavirus."},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.03.035"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1490"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.10.004"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.disamonth.2017.03.020"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20595"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.12744"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03540260059037"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-022-01692-5"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkh029"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2223-y"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240079"},{"key":"e_1_2_7_15_1","volume-title":"Signal Transduction and Targeted Therapy","author":"Zhang X.","year":"2021"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00404"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.05512-11"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(04)03280-5"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2013.843525"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/1098612X17729626"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18233-x"},{"key":"e_1_2_7_22_1","unstructured":"B.Halford \u201cHow Pfizer Scientists Transformed an Old Drug Lead Into a COVID\u201019 Antiviral \u201dChemical & Engineering News \u2010 c&en accessed March 2025 https:\/\/cen.acs.org\/pharmaceuticals\/drug-discovery\/How-Pfizer-scientists-transformed-an-old-drug-lead-into-a-COVID-19-antiviral\/100\/i3."},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201402429"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01002"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16970"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101972"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.10.010"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2017.10.002"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr010182v"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00683"},{"key":"e_1_2_7_31_1","first-page":"561","volume-title":"Expert Opinion on Therapeutic Patents","author":"Rocho F. R.","year":"2022"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2024.01.013"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe0751"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.05.054"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd4596"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.8b00959"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00515"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0897"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3280"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00075"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci300314k"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.445869"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01153"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.11.059"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00612"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70158","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T04:14:18Z","timestamp":1764562458000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.70158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":45,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1002\/ardp.70158"],"URL":"https:\/\/doi.org\/10.1002\/ardp.70158","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"value":"0365-6233","type":"print"},{"value":"1521-4184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]},"assertion":[{"value":"2025-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70158"}}