Non-Nucleoside Inhibitors Decrease Foot-and-Mouth Disease Virus Replication by Blocking the Viral 3Dpol

by Selleckchem | May 10 2023

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.

Comments：

The researchers used double virtual screening and cell-based antiviral approaches to identify potential inhibitors targeting the RNA-dependent RNA polymerase (RdRp) of Foot-and-mouth disease virus (FMDV), an economically important pathogen of cloven-hoofed livestock. RdRp is highly conserved in RNA viruses and compounds that bind to its active site can block viral replication.

The researchers screened 5596 compounds and identified 21 candidates that fit into the 3Dpol active sites through blind- and focus-docking. They then used a BHK-21 cell-based assay to test the antiviral activity of the compounds and found that four of them, NSC217697 (quinoline), NSC670283 (spiro compound), NSC292567 (nigericin), and NSC65850, demonstrated dose-dependent antiviral actions in vitro with EC50 values ranging from 0.78 to 3.49 µM.

Furthermore, 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 affecting 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.

In conclusion, the researchers 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.