The preclinical inhibitor GS441524 in combination with GC376 efficaciously inhibited the proliferation of SARS-CoV-2 in the mouse respiratory tract

Emerg Microbes Infect. 2021 Dec;10(1):481-492. doi: 10.1080/22221751.2021.1899770.

Abstract

The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.

Keywords: SARS-CoV-2; antiviral efficacy; combined application; mouse model; preclinical inhibitor.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • COVID-19 / drug therapy*
  • Cell Proliferation / drug effects
  • Chlorocebus aethiops
  • Coronavirus RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Drug Therapy, Combination
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Prodrugs / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory System / virology*
  • SARS-CoV-2 / drug effects*
  • Vero Cells

Substances

  • Antiviral Agents
  • Prodrugs
  • Coronavirus RNA-Dependent RNA Polymerase

Grant support

This work was supported by National Natural Science Foundation of China Grants 31873020, 31802207 and 31722056, the National Key R&D Program of China (grant number 2018YFC1200601), the Natural Science Foundation of Hubei Province of China (grant number 2020FCA040), the Fundamental Research Funds for the Central Universities (grant number 2662020PY001) and the Applied Technology Research and Development Project of Heilongjiang Province, China (grant number GA20C006).