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Title: Structure-based discovery of foot-and-mouth disease inhibitors that target the 3Dpol RNA-dependent RNA polymerase

Author
item RAI, DEVENDRA - University Of Missouri
item CORNELISON, CEILI - University Of Missouri
item DORST, CHRIS - University Of Missouri
item Schafer, Elizabeth
item MC INTOSH, MARK - University Of Missouri
item Rieder, Aida - Elizabeth
item SINGH, KAMAL - University Of Missouri
item SARAFIANOS, STEFAN - University Of Missouri

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/27/2013
Publication Date: N/A
Citation: N/A

Interpretive Summary: The purpose of this study was to identify and evaluate the efficacy of a chemical library of compounds for their inhibitory activity against the Foot-and-Mouth Disease Virus (FMDV) polymerase, 3Dpol. After the initial screening of the library, four novel compounds were selected based on their activity at suppressing FMDV 3Dpol mediated RNA synthesis. These compounds targeted a pocket near the active site of the virus polymerase. Out of these four, two compounds inhibited the FMDV replication in FMDV infected cells. The computer based docking suggested that the compounds bind in the pocket, which was discovered in our earlier studies published in 2010 (Durk, Rieder, Sarafianos et al. 2010. PLoS One 5:e15049).

Technical Abstract: Foot-and-Mouth Disease Virus (FMDV) primarily targets cloven-hoofed animals. The FMDV outbreak results in significant economic losses. There are currently no available antiviral drugs for Foot-and-Mouth Disease (FMD) treatment, and vaccination needs at least 7 days to effectively trigger the immune system. On the contrary, small molecule antivirals should be able to immediately suppress FMDV replication and contain infection. Using random screening of a chemical library of compounds we have recently identified inhibitors of RNA-Dependent RNA Polymerase of FMDV (3Dpol) and have hypothesized that they bind at a pocket near the active site of the enzyme (5). Here, we validated this new pocket by identifying four new inhibitors based on in silico high-throughput screening followed by in vitro biochemical testing of the compound hits. These compounds (3C3, 8B9, 19B8 and 37B10) inhibited 3Dpol with the inhibition compound with the concentration of 50% (IC50s) between 7 and 14 micro molar (µM). Importantly, 37B10, also inhibited FMDV in cell-based assays. Molecular modeling studies suggest that the compounds bind at the inhibitor binding pocket through both hydrogen-bonding and hydrophobic interactions with binding-site amino acid residues. Moreover, induced-fit docking studies suggest that the inhibitors are accommodated in the binding pocket without change in the conformation of nucleotide trip-phosphate (NTP)-binding residues, consistent with a non-competitive mode of inhibition with respect to NTP substrate.