Newly Proposed Dose of Daclatasvir to Prevent Lethal SARS-CoV-2 Infection in Human Transgenic ACE-2 Mice
Coronavirus disease 2019 (COVID-19) still causes death in elderly and immunocompromised individuals, for whom the sustainability of the vaccine response may be limited. 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's utility against COVID-19.
Authors
- Caroline S. de Freitas (ORCID: https://orcid.org/0000-0001-8100-0472)
- Thiago Moreno L. Souza (ORCID: https://orcid.org/0000-0003-2212-3899)
- Rhaymá do Carmo Silva (ORCID: https://orcid.org/0000-0002-4388-6396)
- João P. B. Viola (ORCID: https://orcid.org/0000-0002-0698-3146)
- Laís Bastos da Fonseca (ORCID: https://orcid.org/0000-0002-2510-8742)
- Douglas Pereira Pinto (ORCID: https://orcid.org/0000-0001-9278-4890)
- Filipe S. Pereira‐Dutra (ORCID: https://orcid.org/0000-0003-1917-2876)
- Carolina Q. Sacramento (ORCID: https://orcid.org/0000-0003-3952-7099)
- Aline de Paula Dias da Silva (ORCID: https://orcid.org/0009-0003-5022-0642)
- Heliana Martins Pereira
- Patrı́cia T. Bozza (ORCID: https://orcid.org/0000-0001-8349-9529)
- Gabriel P. E. Silveira
- João Silveira Moledo Gesto (ORCID: https://orcid.org/0000-0002-4390-2034)
- Natalia Fintelman‐Rodrigues (ORCID: https://orcid.org/0000-0002-2332-8338)
- C. Fernández Blanco
- Marcelo Alves Ferreira (ORCID: https://orcid.org/0000-0003-4181-760X)
- Jairo R. Temerozo (ORCID: https://orcid.org/0000-0002-8092-2149)
- Dumith Chequer Bou‐Habib (ORCID: https://orcid.org/0000-0003-0552-9045)
- Mayara Mattos (ORCID: https://orcid.org/0000-0002-6841-6999)
- André C. Ferreira
- Marcelo Aldrighi Moreira (ORCID: https://orcid.org/0009-0000-7201-9438)
Institutions
- Universidade Iguaçu (BR)
- Instituto Nacional de Câncer - INCA (BR)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- Viruses
- Published
- 2024-11-29
- DOI
- https://doi.org/10.3390/v16121856
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Universidade de São Paulo
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases