{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:33:45Z","timestamp":1788910425069,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfeicoamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison\u2019s inhibitory constant (Ki) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro\u2019s Michaelis\u2013Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro\/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.<\/jats:p>","DOI":"10.3390\/ph15010021","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T01:06:54Z","timestamp":1640567214000},"page":"21","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6211-7659","authenticated-orcid":false,"given":"Ot\u00e1vio Augusto","family":"Chaves","sequence":"first","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-7099","authenticated-orcid":false,"given":"Carolina Q.","family":"Sacramento","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 C.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"Preclinical Research Laboratory, Universidade Igua\u00e7u\u2014UNIG, Nova Iguacu 26260-045, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayara","family":"Mattos","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2332-8338","authenticated-orcid":false,"given":"Natalia","family":"Fintelman-Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8092-2149","authenticated-orcid":false,"given":"Jairo R.","family":"Temerozo","sequence":"additional","affiliation":[{"name":"Laboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"},{"name":"National Institute for Science and Technology on Neuroimmunomodulation (INCT\/NIM), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1306-2644","authenticated-orcid":false,"given":"Leonardo","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9278-4890","authenticated-orcid":false,"given":"Douglas Pereira","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacokinetics, Vice Presidency of Research, and Innovation in Health, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel P. E.","family":"da Silveira","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacokinetics, Vice Presidency of Research, and Innovation in Health, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00eds Bastos","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacokinetics, Vice Presidency of Research, and Innovation in Health, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heliana Martins","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacokinetics, Vice Presidency of Research, and Innovation in Health, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5032-5784","authenticated-orcid":false,"given":"Aluana Santana","family":"Carlos","sequence":"additional","affiliation":[{"name":"Preclinical Research Laboratory, Universidade Igua\u00e7u\u2014UNIG, Nova Iguacu 26260-045, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2045-0813","authenticated-orcid":false,"given":"Joana C.","family":"d\u2019Avila","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Preclinical Research Laboratory, Universidade Igua\u00e7u\u2014UNIG, Nova Iguacu 26260-045, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o P. B.","family":"Viola","sequence":"additional","affiliation":[{"name":"Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rua Andr\u00e9 Cavalcanti 37, 5th Floor, Centro, Rio de Janeiro 20231-050, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5260-2332","authenticated-orcid":false,"given":"Robson Q.","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8349-9529","authenticated-orcid":false,"given":"Patr\u00edcia T.","family":"Bozza","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo Caire","family":"Castro-Faria-Neto","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2212-3899","authenticated-orcid":false,"given":"Thiago Moreno L.","family":"Souza","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil"},{"name":"Center for Technological Development in Health (CDTS), National Institute for Science and Technology on Innovation on Neglected Diseases Neglected Populations (INCT\/IDNP), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/psb.1843","article-title":"COVID-19: A brief history and treatments in development","volume":"31","author":"Chaplin","year":"2020","journal-title":"Prescriber"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.bj.2020.04.007","article-title":"COVID-19: The first documented coronavirus pandemic in history","volume":"43","author":"Liu","year":"2020","journal-title":"Biomed. 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