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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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.

Details

Title
Newly Proposed Dose of Daclatasvir to Prevent Lethal SARS-CoV-2 Infection in Human Transgenic ACE-2 Mice
Author
Mattos, Mayara 1   VIAFID ORCID Logo  ; Sacramento, Carolina Q 1   VIAFID ORCID Logo  ; Ferreira, André C 2   VIAFID ORCID Logo  ; Fintelman-Rodrigues, Natalia 1   VIAFID ORCID Logo  ; Pereira-Dutra, Filipe S 3   VIAFID ORCID Logo  ; Souza de Freitas, Caroline 1   VIAFID ORCID Logo  ; Gesto, João S M 4   VIAFID ORCID Logo  ; Temerozo, Jairo R 5   VIAFID ORCID Logo  ; Aline de Paula Dias Da Silva 1 ; Moreira, Mariana T G 6 ; Silva, Rafael S C 6 ; Silveira, Gabriel P E 6 ; Pinto, Douglas P 6   VIAFID ORCID Logo  ; Pereira, Heliana M 6 ; Fonseca, Laís B 6 ; Marcelo Alves Ferreira 7 ; Blanco, Camilla 1 ; Viola, João P B 8 ; Dumith Chequer Bou-Habib 9   VIAFID ORCID Logo  ; Bozza, Patrícia T 3   VIAFID ORCID Logo  ; Souza, Thiago Moreno L 1 

 Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected] (M.M.); [email protected] (C.Q.S.); [email protected] (A.C.F.); [email protected] (N.F.-R.); [email protected] (F.S.P.-D.); [email protected] (C.S.d.F.); [email protected] (A.d.P.D.D.S.); [email protected] (C.B.); [email protected] (P.T.B.); National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected] 
 Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected] (M.M.); [email protected] (C.Q.S.); [email protected] (A.C.F.); [email protected] (N.F.-R.); [email protected] (F.S.P.-D.); [email protected] (C.S.d.F.); [email protected] (A.d.P.D.D.S.); [email protected] (C.B.); [email protected] (P.T.B.); National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected]; Laboratório de Pesquisas Pré-Clínicas, Departamento de Ciências Biológicas, Universidade Iguaçu, Nova Iguaçu 26275-580, RJ, Brazil 
 Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected] (M.M.); [email protected] (C.Q.S.); [email protected] (A.C.F.); [email protected] (N.F.-R.); [email protected] (F.S.P.-D.); [email protected] (C.S.d.F.); [email protected] (A.d.P.D.D.S.); [email protected] (C.B.); [email protected] (P.T.B.) 
 SESI Innovation Center for Occupational Health, Rio de Janeiro 22735-280, RJ, Brazil; [email protected] (J.S.M.G.); [email protected] (D.C.B.-H.) 
 Laboratório de Pesquisas Sobre o Timo, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil; [email protected]; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil 
 Equivalence and Pharmacokinetics Service (SEFAR), Vice-Presidency of Production and Innovation in Health (VPPIS), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil; [email protected] (M.T.G.M.); [email protected] (R.S.C.S.); [email protected] (G.P.E.S.); [email protected] (D.P.P.); [email protected] (H.M.P.); [email protected] (L.B.F.) 
 National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil; [email protected] 
 Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro 20230-130, RJ, Brazil; [email protected] 
 SESI Innovation Center for Occupational Health, Rio de Janeiro 22735-280, RJ, Brazil; [email protected] (J.S.M.G.); [email protected] (D.C.B.-H.); Laboratório de Pesquisas Sobre o Timo, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-360, RJ, Brazil; [email protected] 
First page
1856
Publication year
2024
Publication date
2024
Publisher
MDPI AG
e-ISSN
19994915
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3149764123
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.