{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:46:44Z","timestamp":1769752004294,"version":"3.49.0"},"reference-count":71,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T00:00:00Z","timestamp":1740873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3503400"],"award-info":[{"award-number":["2023YFC3503400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["ZD2021CY001"],"award-info":[{"award-number":["ZD2021CY001"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["E2G805H"],"award-info":[{"award-number":["E2G805H"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipal Science and Technology Major Project","award":["2023YFC3503400"],"award-info":[{"award-number":["2023YFC3503400"]}]},{"name":"Shanghai Municipal Science and Technology Major Project","award":["ZD2021CY001"],"award-info":[{"award-number":["ZD2021CY001"]}]},{"name":"Shanghai Municipal Science and Technology Major Project","award":["E2G805H"],"award-info":[{"award-number":["E2G805H"]}]},{"name":"SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program","award":["2023YFC3503400"],"award-info":[{"award-number":["2023YFC3503400"]}]},{"name":"SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program","award":["ZD2021CY001"],"award-info":[{"award-number":["ZD2021CY001"]}]},{"name":"SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program","award":["E2G805H"],"award-info":[{"award-number":["E2G805H"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019 (COVID-19) vaccines and therapeutic medications, making the development of effective therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). However, the structural instability of polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing clinical trials, assessing their potential to inhibit SARS-CoV-2 3CLpro. Exifone and benserazide hydrochloride were identified as the inhibitors of SARS-CoV-2 3CLpro among these compounds, using a fluorescence resonance energy transfer (FRET)-based assay. Benserazide hydrochloride was confirmed as a covalent binder to SARS-CoV-2 3CLpro through time-dependent inhibition and kinetic analysis, with its binding mode elucidated by molecular docking. Notably, exifone not only inhibited the protease activity but also blocked the interaction between the host cell receptor angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor binding domain (S-RBD), as identified by surface plasmon resonance (SPR) and flow cytometry. Additionally, exifone demonstrated antiviral activity against various SARS-CoV-2-S pseudovirus variants. In conclusion, the discovery of exifone and benserazide hydrochloride underscores the potential of polyphenols in developing conserved 3CLpro inhibitors for coronaviruses, offering new strategies for the rapid development of effective drugs against both current and future coronavirus pandemics.<\/jats:p>","DOI":"10.3390\/ijms26052243","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:52:16Z","timestamp":1740981136000},"page":"2243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identifying Exifone as a Dual-Target Agent Targeting Both SARS-CoV-2 3CL Protease and the ACE2\/S-RBD Interaction Among Clinical Polyphenolic Compounds"],"prefix":"10.3390","volume":"26","author":[{"given":"Jiani","family":"Lu","sequence":"first","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongtao","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xixiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengcheng","family":"Qin","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"School of Pharmacy, Henan University, Kaifeng 475001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianrong","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihua","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5479-4967","authenticated-orcid":false,"given":"Lili","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41581-022-00652-2","article-title":"Long COVID: Long-term health outcomes and implications for policy and research","volume":"19","author":"Agarwal","year":"2023","journal-title":"Nat. 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