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Antiviral treatments, such as remdesivir or molnupiravir, have demonstrated limited clinical efficacy. Nirmatrelvir, an acute respiratory syndrome coronavirus 2 (SARS-CoV-2) major protease inhibitor, is clinically effective but has been associated with viral rebound and antiviral resistance. It is thus necessary to study novel and repurposed antivirals for the treatment of COVID-19. We previously demonstrated that daclatasvir (DCV), an inhibitor of the hepatitis C virus (HCV) NS5A protein, impairs SARS-CoV-2 replication by targeting viral RNA polymerase and exonuclease, but the doses of DCV used to inhibit the new coronavirus are greater than the standard human plasma exposure for hepatitis C. Because any potential use of DCV against SARS-CoV-2 would be shorter than that reported here and short-term toxicological studies on DCV show that higher doses are tolerable, we searched for doses of DCV that could protect transgenic mice expressing the human ACE2 receptor (K18-hACE-2) from lethal challenge with SARS-CoV-2. We found that a dose of 60 mg\/kg\/day provides this protection by reducing virus replication and virus-induced lung insult. This dose is tolerable in different animal models. Taken together, our data provide preclinical evidence that can support phase I clinical trials to confirm the safety, tolerability, and pharmacokinetics of new doses of daclatasvir for a short duration in humans to further advance this compound\u2019s utility against COVID-19.<\/jats:p>","DOI":"10.3390\/v16121856","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T02:57:08Z","timestamp":1732849028000},"page":"1856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Newly Proposed Dose of Daclatasvir to Prevent Lethal SARS-CoV-2 Infection in Human Transgenic ACE-2 Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6841-6999","authenticated-orcid":false,"given":"Mayara","family":"Mattos","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, 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":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9064-2351","authenticated-orcid":false,"given":"Andr\u00e9 C.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"Laborat\u00f3rio de Pesquisas Pr\u00e9-Cl\u00ednicas, Departamento de Ci\u00eancias Biol\u00f3gicas, Universidade Igua\u00e7u, Nova Igua\u00e7u 26275-580, RJ, 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":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1917-2876","authenticated-orcid":false,"given":"Filipe S.","family":"Pereira-Dutra","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8100-0472","authenticated-orcid":false,"given":"Caroline Souza","family":"de Freitas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"},{"name":"National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT\/IDPN), Center for Technological Development in Health (CDTS), Funda\u00e7\u00e3o Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4390-2034","authenticated-orcid":false,"given":"Jo\u00e3o S. 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