Journal
EMERGING MICROBES & INFECTIONS
Volume 10, Issue 1, Pages 481-492Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/22221751.2021.1899770
Keywords
SARS-CoV-2; mouse model; preclinical inhibitor; combined application; antiviral efficacy
Categories
Funding
- National Natural Science Foundation of China [31722056, 31802207]
- National Key RAMP
- D Program of China [2018YFC1200601]
- Natural Science Foundation of Hubei Province of China [2020FCA040]
- Fundamental Research Funds for the Central Universities [2662020PY001]
- Applied Technology Research and Development Project of Heilongjiang Province, China [GA20C006]
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The study found that in a mouse model infected with SARS-CoV-2, GS441524 effectively blocked the replication of the virus through intranasal and intramuscular treatment, whereas the efficacy of GC376 was weaker. A low-dose combination of GS441524 and GC376 could effectively protect mice from infection and showed a synergistic effect when used together.
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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