Related Experiment Video
Updated: Jun 3, 2025
Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
Newly Proposed Dose of Daclatasvir to Prevent Lethal SARS-CoV-2 Infection in Human Transgenic ACE-2 Mice
Mayara Mattos1,2, Carolina Q Sacramento1,2, André C Ferreira1,2,3
1Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil.
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.
Insights
Daclatasvir (DCV) shows promise as a COVID-19 treatment. A specific dose protected mice from lethal SARS-CoV-2 infection by reducing viral replication and lung damage, supporting further clinical trials.
Area of Science:
- Virology
- Infectious Diseases
- Pharmacology
Background:
- COVID-19 remains a threat, especially to vulnerable populations with waning vaccine immunity.
- Existing antivirals like remdesivir and molnupiravir have limited efficacy, and nirmatrelvir faces challenges with viral rebound and resistance.
- Novel and repurposed antiviral strategies are crucial for effective COVID-19 treatment.
Purpose of the Study:
- To investigate daclatasvir (DCV), a hepatitis C virus (HCV) NS5A inhibitor, as a potential treatment for COVID-19.
- To determine if higher, tolerable doses of DCV could protect against SARS-CoV-2 infection in a preclinical model.
- To provide evidence supporting Phase I clinical trials for DCV in COVID-19 patients.
Main Methods:
- Utilized transgenic mice (K18-hACE-2) expressing the human ACE2 receptor for SARS-CoV-2 challenge.
- Administered a dose of 60 mg/kg/day of daclatasvir (DCV) to assess its protective effects.
- Evaluated viral replication, lung pathology, and overall survival in treated versus control groups.
Main Results:
- A daclatasvir (DCV) dose of 60 mg/kg/day significantly protected K18-hACE-2 mice from lethal SARS-CoV-2 challenge.
- DCV treatment reduced viral replication in the lungs.
- The chosen dose of DCV mitigated virus-induced lung injury and was found to be tolerable in animal models.
Conclusions:
- Preclinical data demonstrate that daclatasvir (DCV) at 60 mg/kg/day is effective in protecting against lethal SARS-CoV-2 infection in a relevant mouse model.
- The findings support the investigation of higher, short-term doses of daclatasvir for COVID-19 treatment.
- Further clinical trials are warranted to confirm the safety, tolerability, and pharmacokinetics of daclatasvir in humans for COVID-19 therapy.
