{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:01:09Z","timestamp":1790733669307,"version":"4.1.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Nucleotide analogues (NA) are currently employed for treatment of several viral diseases, including COVID-19. NA prodrugs are intracellularly activated to the 5\u2032-triphosphate form. They are incorporated into the viral RNA by the viral polymerase (SARS-CoV-2 nsp12), terminating or corrupting RNA synthesis. For Coronaviruses, natural resistance to NAs is provided by a viral 3\u2032-to-5\u2032 exonuclease heterodimer nsp14\/nsp10, which can remove terminal analogues. Here, we show that the replacement of the \u03b1-phosphate of Bemnifosbuvir 5\u2032-triphosphate form (AT-9010) by an \u03b1-thiophosphate renders it resistant to excision. The resulting \u03b1-thiotriphosphate, AT-9052, exists as two epimers (RP\/SP). Through co-crystallization and activity assays, we show that the Sp isomer is preferentially used as a substrate by nucleotide diphosphate kinase (NDPK), and by SARS-CoV-2 nsp12, where its incorporation causes immediate chain-termination. The same -Sp isomer, once incorporated by nsp12, is also totally resistant to the excision by nsp10\/nsp14 complex. However, unlike AT-9010, AT-9052-RP\/SP no longer inhibits the N-terminal nucleotidylation domain of nsp12. We conclude that AT-9052-Sp exhibits a unique mechanism of action against SARS-CoV-2. Moreover, the thio modification provides a general approach to rescue existing NAs whose activity is hampered by coronavirus proofreading capacity.<\/jats:p>","DOI":"10.1093\/nar\/gkad1194","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T16:39:13Z","timestamp":1702399153000},"page":"1325-1340","source":"Crossref","is-referenced-by-count":16,"title":["An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4290-8247","authenticated-orcid":false,"given":"Ashleigh","family":"Shannon","sequence":"first","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Chazot","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5636-8208","authenticated-orcid":false,"given":"Mikael","family":"Feracci","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Falcou","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Fattorini","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Selisko","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Good","sequence":"additional","affiliation":[{"name":"ATEA Pharmaceuticals, Inc. , 225 Franklin St., Suite 2100 , Boston , MA\u00a0 02110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Moussa","sequence":"additional","affiliation":[{"name":"ATEA Pharmaceuticals, Inc. , 225 Franklin St., Suite 2100 , Boston , MA\u00a0 02110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Sommadossi","sequence":"additional","affiliation":[{"name":"ATEA Pharmaceuticals, Inc. , 225 Franklin St., Suite 2100 , Boston , MA\u00a0 02110 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8351-4992","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Ferron","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"},{"name":"European Virus Bioinformatics Center , Leutragraben 1 , 07743\u00a0 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Alvarez","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-1991","authenticated-orcid":false,"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[{"name":"AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 , Marseille\u00a0 Cedex 09 , France"},{"name":"European Virus Bioinformatics Center , Leutragraben 1 , 07743\u00a0 Jena , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"2024020908492622500_B1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. 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