Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2-P4 study

Journal of Enzyme Inhibition and Medicinal Chemistry
Melgious Jin Yan AngC S Brian Chia

Abstract

Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 ± 0.4 versus 7.3 ± 0.8 μM). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities.

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Citations

Sep 21, 2016·Scientific Reports·Yong Wah TanJustin Jang Hann Chu
Sep 9, 2017·Expert Opinion on Therapeutic Patents·Hyemin LeeSung-Hoon Kim
Mar 14, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yixuan WangZhuorong Li

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