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

文献类型： 外文期刊

第一作者： Shi, Yuejun

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

作者机构：

关键词： SARS-CoV-2; mouse model; preclinical inhibitor; combined application; antiviral efficacy

期刊名称：EMERGING MICROBES & INFECTIONS （ 影响因子：5.776； 五年影响因子：6.197 ）

ISSN：

年卷期： 2021 年 10 卷 1 期

页码：

收录情况： SCI

摘要： 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.

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