Abstract
Foot-and-mouth disease virus (FMDV), an economically important pathogen of cloven-hoofed livestock, is a positive-sense, single-stranded RNA virus classified in the Picornaviridae family. RNA-dependent RNA polymerase (RdRp) of RNA viruses is highly conserved. Compounds that bind to the RdRp active site can block viral replication. Herein, we combined double virtual screenings and cell-based antiviral approaches to screen and identify potential inhibitors targeting FMDV RdRp (3Dpol). From 5596 compounds, the blind- followed by focus-docking filtered 21 candidates fitting in the 3Dpol active sites. Using the BHK-21 cell-based assay, we found that four compounds—NSC217697 (quinoline), NSC670283 (spiro compound), NSC292567 (nigericin), and NSC65850—demonstrated dose-dependent antiviral actions in vitro with the EC50 ranging from 0.78 to 3.49 µM. These compounds could significantly block FMDV 3Dpol activity in the cell-based 3Dpol inhibition assay with small IC50 values ranging from 0.8 nM to 0.22 µM without an effect on FMDV’s main protease, 3Cpro. The 3Dpol inhibition activities of the compounds were consistent with the decreased viral load and negative-stranded RNA production in a dose-dependent manner. Conclusively, we have identified potential FMDV 3Dpol inhibitors that bound within the enzyme active sites and blocked viral replication. These compounds might be beneficial for FMDV or other picornavirus treatment.
Funder
National Research Council of Thailand
Kasetsart University Research and Development Institute
Subject
Virology,Infectious Diseases
Reference41 articles.
1. Foot-and-mouth disease: Past, present and future;Jamal;Vet. Res.,2013
2. Towards improvements in foot-and-mouth disease vaccine performance;Belsham;Acta Vet. Scand.,2020
3. Venkataraman, S., Prasad, B., and Selvarajan, R. (2018). RNA dependent RNA polymerases: Insights from structure, function and evolution. Viruses, 10.
4. A comparison of viral RNA-dependent RNA polymerases;Ferrerorta;Curr. Opin. Struct. Biol.,2006
5. Multifunctionality of a picornavirus polymerase domain: Nuclear localization signal and nucleotide recognition;Caridi;J. Virol.,2015
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献