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

Yuejun Shi; Lei Shuai; Zhiyuan Wen; Chong Wang; Yuanyuan Yan; Zhe Jiao; Fenglin Guo; Zhen F Fu; Huanchun Chen; Zhigao Bu; Guiqing Peng

doi:10.1080/22221751.2021.1899770

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.

Authors

Yuejun Shi^{1

2}, Lei Shuai³, Zhiyuan Wen³, Chong Wang³, Yuanyuan Yan^{1

2}, Zhe Jiao^{1

2}, Fenglin Guo^{1

2}, Zhen F Fu^{1

2}, Huanchun Chen^{1

2}, Zhigao Bu^{3

4}, Guiqing Peng^{1

2}

Affiliations

¹ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People's Republic of China.
² Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, People's Republic of China.
³ State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.
⁴ National High Containment Laboratory for Animal Diseases Control and Prevention, Harbin, People's Republic of China.

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 Treatment*
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

Grants and funding

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).