In silico and in vitro analysis of small molecules and natural compounds targeting the 3CL protease of feline infectious peritonitis virus

Lay Summary

According to information announced by WHO and China CDC, a new type of coronavirus (novel coronavirus 2019, nCoV-2019 and also called as SARS-CoV-2) has been identified from cases during the SARS-liked outbreak in Wuhan City. Coronaviruses is in the family Coronaviridae. During two decades, two zoonotic coronaviruses, SARS-CoV and MERS-CoV, were reported, SARS-CoV in 2002 in China and MERS-CoV in 2012 in Saudi Arabia Both transmitted from animals to infect and cause severe respiratory illness in human. 
Over a decade, researchers worldwide have been vigorously developing an effective antiviral agent, both broad-spectrum and specific target drug. 3C-like protease (3CLpro) is one of the antiviral target for combatting CoV infections. We recently identified the candidate compounds against Feline CoV (one of CoV infection in cats that also belongs to
 Coronaviridae), which were strongly inhibit 3CLpro activity directly at the catalytic dyads (His41 and Cys144) and significantly reduced FIP infection in vitro. We hope that our finding could add up the number of anti-CoV agents for an effective CoV prevention and treatment to alleviate the severe symptoms and decrease the fatal cases.

Abstract

The computational search of chemical libraries has been used as a powerful tool for the rapid discovery of candidate compounds. To find small molecules with anti-feline infectious peritonitis virus (FIPV) properties, we utilized a virtual screening technique to identify the active site on the viral protease for the binding of the available natural compounds. The protease 3CL (3CLpro) plays an important role in the replication cycle of FIPV and other viruses within the family Coronaviridae. The 15 best-ranked candidate consensus compounds, based on three docking tools, were evaluated for further assays. The protease inhibitor assay on recombinant FIPV 3CLpro was performed to screen the inhibitory effect of the candidate compounds with IC50 ranging from 6.36 ± 2.15 to 78.40 ± 2.60 μM. As determined by the cell-based assay, the compounds NSC345647, NSC87511, and NSC343256 showed better EC50 values than the broad-spectrum antiviral drug ribavirin and the protease inhibitor lopinavir, under all the test conditions including pre-viral entry, post-viral entry, and prophylactic activity. The NSC87511 particularly yielded the best selective index (>4; range of SI = 13.80–22.90). These results indicated that the natural small-molecular compounds specifically targeted the 3CLpro of FIPV and inhibited its replication. Structural modification of these compounds may generate a higher anti-viral potency for the further development of a novel therapy against FIP.

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