{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:28:04Z","timestamp":1787128084120,"version":"build-2736575974"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"2","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-001"},{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-009"},{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"}],"funder":[{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-IA-107-L03"],"award-info":[{"award-number":["AS-IA-107-L03"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-IA-110-L02"],"award-info":[{"award-number":["AS-IA-110-L02"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST-107-2113-M-001-018"],"award-info":[{"award-number":["MOST-107-2113-M-001-018"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2\u201316 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease or the RNA-dependent RNA polymerase. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance and\/or evasion of antiviral drugs. We show that the clinically safe Zn-ejector drugs disulfiram and ebselen can target conserved Zn2+ sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram\/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram\/ebselen, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multitargeting strategy, which can be applied to any type of coronavirus with conserved Zn2+ sites.<\/jats:p>","DOI":"10.1021\/acsptsci.1c00022","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T12:03:25Z","timestamp":1616760205000},"page":"898-907","source":"Crossref","is-referenced-by-count":66,"title":["Synergistic Inhibition of SARS-CoV\u20112 Replication\nUsing Disulfiram\/Ebselen and\nRemdesivir"],"prefix":"10.1021","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8055-3104","authenticated-orcid":true,"given":"Ting","family":"Chen","sequence":"first","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Yin","family":"Fei","sequence":"additional","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Sargsyan","sequence":"additional","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-5546","authenticated-orcid":true,"given":"Chun-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"National Health Research Institutes , , ,","place":["Miaoli, Taiwan, 350"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna S.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9077-7769","authenticated-orcid":true,"given":"Carmay","family":"Lim","sequence":"additional","affiliation":[{"name":"Academia Sinica , , ,","place":["Taipei, Taiwan, 115"]},{"name":"National Tsing Hua University , , ,","place":["Hsinchu, Taiwan, 300"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"2026081904085146700_cit1","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1001\/jama.2020.22813","article-title":"Therapy for early COVID-19: A critical\nneed","volume":"324","author":"Kim","year":"2020","journal-title":"JAMA"},{"key":"2026081904085146700_cit2","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1056\/NEJMoa2029849","article-title":"SARS-CoV-2\nneutralizing antibody LY-CoV555 in outpatients\nwith Covid-19","volume":"384","author":"Chen","year":"2021","journal-title":"N. 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