Key result
Compound 9, containing a P2 ring-constrained phenylalanine analog, was two-fold more potent than Rupintrivir against the EV71 3C protease (IC50 3.4 ± 0.4 vs 7.3 ± 0.8 μM).
Absolute Event Rate: 3.4% vs 7.3%
Employing geometrically constrained residues in peptide-based protease inhibitors can enhance their inhibitory activities against EV71 3C protease.
May guide EV71 3C inhibitor design; leaves open in vivo efficacy and clinical translation.
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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Ang et al. (2015) studied Enterovirus 71 (EV71) infection. Rupintrivir analogs (compound 9) vs. Rupintrivir was evaluated on Inhibitory activity against EV71 3C protease (IC50). Compound 9, containing a P2 ring-constrained phenylalanine analog, was two-fold more potent than Rupintrivir against the EV71 3C protease (IC50 3.4 ± 0.4 vs 7.3 ± 0.8 μM).
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