{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T15:06:23Z","timestamp":1758812783424,"version":"3.41.2"},"reference-count":46,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2020M3A9I2081687"],"award-info":[{"award-number":["2020M3A9I2081687"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2020M3A9I2108564"],"award-info":[{"award-number":["2020M3A9I2108564"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003704","name":"Korea Research Institute of Chemical Technology","doi-asserted-by":"crossref","award":["KK2432-10"],"award-info":[{"award-number":["KK2432-10"]}],"id":[{"id":"10.13039\/501100003704","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 \u00b5M against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg\/kg\/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.00341-24","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T13:00:43Z","timestamp":1715691643000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of endocytic uptake of severe acute respiratory syndrome coronavirus 2 and endo-lysosomal acidification by diphenoxylate"],"prefix":"10.1128","author":[{"given":"Jin Soo","family":"Shin","sequence":"first","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yejin","family":"Jang","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-Su","family":"Kim","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunhye","family":"Jung","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myoung Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byungil","family":"Kim","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunjoo","family":"Ahn","sequence":"additional","affiliation":[{"name":"Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeonju","family":"Shin","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su San","family":"Jang","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang Soo","family":"Yun","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jongman","family":"Yoo","sequence":"additional","affiliation":[{"name":"CHA Organoid Research Center, CHA University, Seongnam, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Chang","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, The Research Institute, Konkuk University School of Medicine, Seoul, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-1832","authenticated-orcid":false,"given":"Soo Bong","family":"Han","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"},{"name":"Medicinal Chemistry and Pharmacology, University of Science and Technology (UST), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2851-5298","authenticated-orcid":true,"given":"Meehyein","family":"Kim","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_3_3_2_2","DOI":"10.1016\/j.chom.2020.02.001"},{"unstructured":"WHO. 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