Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model

Sci Rep. 2021 May 5;11(1):9609. doi: 10.1038/s41598-021-89013-w.

Abstract

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mpro inhibitor with antiviral activity against SARS-CoV-2 in vitro. Using the K18-hACE2 mouse model, the in vivo antiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18-hACE2 mice. Overall outcome of clinical symptoms and survival upon SARS-CoV-2 challenge were not improved in mice treated with GC-376 compared to controls. The treatment with GC-376 slightly improved survival from 0 to 20% in mice challenged with a high virus dose at 105 TCID50/mouse. Most notably, GC-376 treatment led to milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls in mice challenged with a low virus dose at 103 TCID50/mouse. This was particularly the case in the brain where a 5-log reduction in viral titers was observed in GC-376 treated mice compared to vehicle controls. This study supports the notion that GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection and that the K18-hACE2 mouse model is suitable to study antiviral therapies against SARS-CoV-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics*
  • Animals
  • Antiviral Agents / pharmacology*
  • Brain / drug effects
  • Brain / pathology
  • COVID-19 / drug therapy*
  • COVID-19 / pathology
  • COVID-19 / virology
  • Carbonates / pharmacology*
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Female
  • Keratin-18 / genetics
  • Leucine / pharmacology*
  • Lung / drug effects
  • Lung / pathology
  • Lung / virology
  • Mice, Transgenic
  • Sulfonic Acids / pharmacology*
  • Vero Cells
  • Viral Load

Substances

  • Antiviral Agents
  • Carbonates
  • KRT18 protein, human
  • Keratin-18
  • Sulfonic Acids
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Leucine
  • GC-376

Supplementary concepts

  • COVID-19 drug treatment