{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:25:48Z","timestamp":1789669548779,"version":"4.0.1"},"reference-count":49,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104372"],"award-info":[{"award-number":["82104372"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32200131"],"award-info":[{"award-number":["32200131"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Acta Pharmaceutica Sinica B"],"published-print":{"date-parts":[[2025,11]]},"DOI":"10.1016\/j.apsb.2025.09.033","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:24:53Z","timestamp":1758605093000},"page":"5789-5802","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting SARS-CoV-2 main protease for the discovery of a broad-spectrum COVID-19 inhibitor by intensive multi-tiered validation"],"prefix":"10.1016","volume":"15","author":[{"given":"Min","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipeng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-6046","authenticated-orcid":false,"given":"Yuefei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihe","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.apsb.2025.09.033_bib1","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1074\/jbc.RA120.013679","article-title":"Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency","volume":"295","author":"Gordon","year":"2020","journal-title":"J Biol Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/cid\/ciac180","article-title":"Molnupiravir and nirmatrelvir-ritonavir: oral coronavirus disease 2019 antiviral drugs","volume":"76","author":"Saravolatz","year":"2023","journal-title":"Clin Infect Dis"},{"key":"10.1016\/j.apsb.2025.09.033_bib3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/cid\/ciac443","article-title":"Effectiveness of paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients","volume":"76","author":"Najjar-Debbiny","year":"2023","journal-title":"Clin Infect Dis"},{"key":"10.1016\/j.apsb.2025.09.033_bib4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1001\/jama.2021.11330","article-title":"Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis","volume":"326","author":"Shankar-Hari","year":"2021","journal-title":"JAMA"},{"key":"10.1016\/j.apsb.2025.09.033_bib5","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2023.104559","article-title":"Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance","volume":"91","author":"Ip","year":"2023","journal-title":"EBioMedicine"},{"key":"10.1016\/j.apsb.2025.09.033_bib6","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1021\/acscentsci.3c00538","article-title":"Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir","volume":"9","author":"Hu","year":"2023","journal-title":"ACS Cent Sci"},{"key":"10.1016\/j.apsb.2025.09.033_bib7","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.add7197","article-title":"Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system","volume":"8","author":"Zhou","year":"2022","journal-title":"Sci Adv"},{"key":"10.1016\/j.apsb.2025.09.033_bib8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/HM9.0000000000000048","article-title":"Tea as a natural gift for discovering antiviral candidates","volume":"2","author":"Wang","year":"2022","journal-title":"Acupunct Herb Med"},{"key":"10.1016\/j.apsb.2025.09.033_bib9","doi-asserted-by":"crossref","first-page":"7561","DOI":"10.1021\/acs.jmedchem.2c00303","article-title":"Progress and challenges in targeting the SARS-CoV-2 papain-like protease","volume":"65","author":"Tan","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib10","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.adm9724","article-title":"Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model","volume":"383","author":"Tan","year":"2024","journal-title":"Science"},{"key":"10.1016\/j.apsb.2025.09.033_bib11","doi-asserted-by":"crossref","first-page":"7785","DOI":"10.1021\/acs.jmedchem.2c02120","article-title":"Structure-based discovery of inhibitors of the SARS-CoV-2 nsp14 N7-methyltransferase","volume":"66","author":"Singh","year":"2023","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib12","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abf8711","article-title":"Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking","volume":"7","author":"Schuller","year":"2021","journal-title":"Sci Adv"},{"key":"10.1016\/j.apsb.2025.09.033_bib13","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.apsb.2025.09.033_bib14","article-title":"Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2","volume":"119","author":"Zhao","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.apsb.2025.09.033_bib15","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"10.1016\/j.apsb.2025.09.033_bib16","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"10.1016\/j.apsb.2025.09.033_bib17","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"10.1016\/j.apsb.2025.09.033_bib18","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.3390\/antiox12122093","article-title":"Global profiling of the antioxidant constituents in chebulae fructus based on an integrative strategy of UHPLC\/IM-QTOF\u2013MS, MS\/MS molecular networking, and spectrum-effect correlation","volume":"12","author":"Wang","year":"2023","journal-title":"Antioxidants"},{"key":"10.1016\/j.apsb.2025.09.033_bib19","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.scib.2020.10.018","article-title":"Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode","volume":"66","author":"Li","year":"2021","journal-title":"Sci Bull"},{"key":"10.1016\/j.apsb.2025.09.033_bib20","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/s41401-020-0483-6","article-title":"Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients","volume":"41","author":"Su","year":"2020","journal-title":"Acta Pharmacol Sin"},{"key":"10.1016\/j.apsb.2025.09.033_bib21","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41594-020-0440-6","article-title":"Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug Carmofur","volume":"27","author":"Jin","year":"2020","journal-title":"Nat Struct Mol Biol"},{"key":"10.1016\/j.apsb.2025.09.033_bib22","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"10.1016\/j.apsb.2025.09.033_bib23","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00018-022-04488-8","article-title":"Neuronal-specific septin-3 binds Atg8\/LC3B, accumulates and localizes to autophagosomes during induced autophagy","volume":"79","author":"T\u00f3th","year":"2022","journal-title":"Cell Mol Life Sci"},{"key":"10.1016\/j.apsb.2025.09.033_bib24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"10.1016\/j.apsb.2025.09.033_bib25","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J Appl Crystallogr"},{"key":"10.1016\/j.apsb.2025.09.033_bib26","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1107\/S2059798319011471","article-title":"Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix","volume":"75","author":"Liebschner","year":"2019","journal-title":"Acta Crystallogr D"},{"key":"10.1016\/j.apsb.2025.09.033_bib27","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"10.1016\/j.apsb.2025.09.033_bib28","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards automated crystallographic structure refinement with phenix.refine","volume":"68","author":"Afonine","year":"2012","journal-title":"Acta Crystallogr D"},{"key":"10.1016\/j.apsb.2025.09.033_bib29","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/2472555220916168","article-title":"Applied biophysical methods in fragment-based drug discovery","volume":"25","author":"Coyle","year":"2020","journal-title":"SLAS Discov"},{"key":"10.1016\/j.apsb.2025.09.033_bib30","doi-asserted-by":"crossref","first-page":"12197","DOI":"10.1021\/acs.jafc.1c03521","article-title":"Inhibitory effects and surface plasmon resonance-based binding affinities of dietary hydrolyzable tannins and their gut microbial metabolites on SARS-CoV-2 main protease","volume":"69","author":"Li","year":"2021","journal-title":"J Agric Food Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s10858-014-9848-9","article-title":"Comparison of the sensitivities of WaterLOGSY and saturation transfer difference NMR experiments","volume":"60","author":"Antanasijevic","year":"2014","journal-title":"J Biomol NMR"},{"key":"10.1016\/j.apsb.2025.09.033_bib32","first-page":"477","volume":"vol 615","author":"Huang","year":"2019"},{"key":"10.1016\/j.apsb.2025.09.033_bib33","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1021\/jo971176v","article-title":"NMR chemical shifts of common laboratory solvents as trace impurities","volume":"62","author":"Gottlieb","year":"1997","journal-title":"J Org Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib34","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1126\/science.abf1611","article-title":"SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model","volume":"371","author":"Qiao","year":"2021","journal-title":"Science"},{"key":"10.1016\/j.apsb.2025.09.033_bib35","doi-asserted-by":"crossref","first-page":"23544","DOI":"10.1002\/anie.202010316","article-title":"Allosteric inhibition of the SARS-CoV-2 main protease: insights from mass spectrometry based assays","volume":"59","author":"El-Baba","year":"2020","journal-title":"Angew Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib36","doi-asserted-by":"crossref","first-page":"6499","DOI":"10.1021\/acs.jmedchem.2c00117","article-title":"Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19","volume":"65","author":"Unoh","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib37","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.1021\/acs.jmedchem.1c00509","article-title":"Expedited approach toward the rational design of noncovalent SARS-CoV-2 main protease inhibitors","volume":"65","author":"Kitamura","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2025.09.033_bib38","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1021\/acscentsci.2c01359","article-title":"Development of highly potent noncovalent inhibitors of SARS-CoV-2 3CLpro","volume":"9","author":"Hou","year":"2023","journal-title":"ACS Cent Sci"},{"key":"10.1016\/j.apsb.2025.09.033_bib39","article-title":"Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro","volume":"190","author":"Du","year":"2021","journal-title":"Antivil res"},{"key":"10.1016\/j.apsb.2025.09.033_bib40","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.chom.2022.08.003","article-title":"Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites","volume":"30","author":"Iketani","year":"2022","journal-title":"Cell Host Microbe"},{"key":"10.1016\/j.apsb.2025.09.033_bib41","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.1016\/j.apsb.2022.07.017","article-title":"Schaftoside inhibits 3CLpro and PLpro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19","volume":"12","author":"Yi","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"10.1016\/j.apsb.2025.09.033_bib42","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.apsb.2023.08.004","article-title":"Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors","volume":"14","author":"Song","year":"2024","journal-title":"Acta Pharm Sin B"},{"key":"10.1016\/j.apsb.2025.09.033_bib43","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.1016\/j.apsb.2024.05.026","article-title":"Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics","volume":"14","author":"Chan","year":"2024","journal-title":"Acta Pharm Sin B"},{"key":"10.1016\/j.apsb.2025.09.033_bib44","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.1128\/JVI.01492-10","article-title":"Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein-glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell-to-cell spread","volume":"85","author":"Lin","year":"2011","journal-title":"J Virol"},{"key":"10.1016\/j.apsb.2025.09.033_bib45","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12906-017-1620-8","article-title":"Anti-HSV-2 activity of Terminalia chebula Retz extract and its constituents, chebulagic and chebulinic acids","volume":"17","author":"Kesharwani","year":"2017","journal-title":"BMC Compl Alternative Med"},{"key":"10.1016\/j.apsb.2025.09.033_bib46","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3389\/fmicb.2020.00182","article-title":"Identification of chebulinic acid and chebulagic acid as novel influenza viral neuraminidase inhibitors","volume":"11","author":"Li","year":"2020","journal-title":"Front Microbiol"},{"key":"10.1016\/j.apsb.2025.09.033_bib47","doi-asserted-by":"crossref","first-page":"4024","DOI":"10.1080\/07391102.2022.2060862","article-title":"Chebulinic and chebulagic acid binding with serum proteins: biophysical and molecular docking approach","volume":"41","author":"Yeggoni","year":"2023","journal-title":"J Biomol Struct Dyn"},{"key":"10.1016\/j.apsb.2025.09.033_bib48","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/1471-2180-13-187","article-title":"Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry","volume":"13","author":"Lin","year":"2013","journal-title":"BMC Microbiol"},{"key":"10.1016\/j.apsb.2025.09.033_bib49","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic options for the 2019 novel coronavirus (2019-nCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat Rev Drug Discov"}],"container-title":["Acta Pharmaceutica Sinica B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211383525006409?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211383525006409?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:37:17Z","timestamp":1777624637000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2211383525006409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":49,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["S2211383525006409"],"URL":"https:\/\/doi.org\/10.1016\/j.apsb.2025.09.033","relation":{},"ISSN":["2211-3835"],"issn-type":[{"value":"2211-3835","type":"print"}],"subject":[],"published":{"date-parts":[[2025,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Targeting SARS-CoV-2 main protease for the discovery of a broad-spectrum COVID-19 inhibitor by intensive multi-tiered validation","name":"articletitle","label":"Article Title"},{"value":"Acta Pharmaceutica Sinica B","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.apsb.2025.09.033","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.","name":"copyright","label":"Copyright"}]}}