{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:06:02Z","timestamp":1787889962729,"version":"build-2784847793"},"reference-count":41,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences (United States)","doi-asserted-by":"publisher","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside\/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 \u00b5M TAF, TDF, FTC, or 500 \u00b5M TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.<\/jats:p>","DOI":"10.3390\/molecules27134212","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:21:50Z","timestamp":1656634910000},"page":"4212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Nucleoside\/Nucleotide Analogs Tenofovir and Emtricitabine Are Inactive against SARS-CoV-2"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4837-1911","authenticated-orcid":false,"given":"Joy Y.","family":"Feng","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venice","family":"Du Pont","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Babusis","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-6201","authenticated-orcid":false,"given":"Calvin J.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egor P.","family":"Tchesnokov","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5492-0652","authenticated-orcid":false,"given":"Jason K.","family":"Perry","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Duong","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arya","family":"Vijjapurapu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Chan","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cal","family":"Cohen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Juneja","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Cihlar","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"G\u00f6tte","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Bilello","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/nrmicro3143","article-title":"A decade after SARS: Strategies for controlling emerging coronaviruses","volume":"11","author":"Graham","year":"2013","journal-title":"Nat. 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