Your browser doesn't support javascript.
loading
Adaptive Mutation in the Main Protease Cleavage Site of Feline Coronavirus Renders the Virus More Resistant to Main Protease Inhibitors.
Jiao, Zhe; Yan, Yuanyuan; Chen, Yixi; Wang, Gang; Wang, Xiaowei; Li, Lisha; Yang, Mengfang; Hu, Xiaoshuai; Guo, Yilin; Shi, Yuejun; Peng, Guiqing.
Afiliação
  • Jiao Z; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
  • Yan Y; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
  • Chen Y; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
  • Wang G; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
  • Wang X; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
  • Li L; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
  • Yang M; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
  • Hu X; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
  • Guo Y; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
  • Shi Y; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
  • Peng G; State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural Universitygrid.35155.37, Wuhan, China.
J Virol ; 96(17): e0090722, 2022 09 14.
Article em En | MEDLINE | ID: mdl-36000844
The rapid global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused serious health problems, highlighting the urgent need for antiviral drugs. The viral main protease (Mpro) plays an important role in viral replication and thus remains the target of choice for the prevention or treatment of several viral diseases due to high sequence and structural conservation. Prolonged use of viral protease inhibitors can lead to the development of mutants resistant to those inhibitors and to many of the available antiviral drugs. Here, we used feline infectious peritonitis virus (FIPV) as a model to investigate its development of resistance under pressure from the Mpro inhibitor GC376. Passage of wild-type (WT) FIPV in the presence of GC376 selected for a mutation in the nsp12 region where Mpro cleaves the substrate between nsp12 and nsp13. This mutation confers up to 3-fold resistance to GC376 and nirmatrelvir, as determined by EC50 assay. In vitro biochemical and cellular experiments confirmed that FIPV adapts to the stress of GC376 by mutating the nsp12 and nsp13 hydrolysis site to facilitate cleavage by Mpro and release to mediate replication and transcription. Finally, we demonstrate that GC376 cannot treat FIP-resistant mutants that cause FIP in animals. Taken together, these results suggest that Mpro affects the replication of coronaviruses (CoVs) and the drug resistance to GC376 by regulating the amount of RdRp from a distant site. These findings provide further support for the use of an antiviral drug combination as a broad-spectrum therapy to protect against contemporary and emerging CoVs. IMPORTANCE CoVs cause serious human infections, and antiviral drugs are currently approved to treat these infections. The development of protease-targeting therapeutics for CoV infection is hindered by resistance mutations. Therefore, we should pay attention to its resistance to antiviral drugs. Here, we identified possible mutations that lead to relapse after clinical treatment of FIP. One amino acid substitution in the nsp12 polymerase at the Mpro cleavage site provided low-level resistance to GC376 after selection exposure to the GC376 parental nucleoside. Resistance mutations enhanced FIPV viral fitness in vitro and attenuated the therapeutic effect of GC376 in an animal model of FIPV infection. Our research explains the evolutionary characteristics of coronaviruses under antiviral drugs, which is helpful for a more comprehensive understanding of the molecular basis of virus resistance and provides important basic data for the effective prevention and control of CoVs.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Inibidores de Proteases / Coronavirus Felino / Farmacorresistência Viral / Proteases 3C de Coronavírus / Mutação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Virol Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Inibidores de Proteases / Coronavirus Felino / Farmacorresistência Viral / Proteases 3C de Coronavírus / Mutação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Virol Ano de publicação: 2022 Tipo de documento: Article