title: Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2-P4 study.
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.
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Melgious J Y
authors: MJ
authors: Ang
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Qiu Ying
authors: QY
authors: Lau
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Fui Mee
authors: FM
authors: Ng
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Siew Wen
authors: SW
authors: Then
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Anders
authors: A
authors: Poulsen
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Yuen Kuen
authors: YK
authors: Cheong
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Zi Xian
authors: ZX
authors: Ngoh
authors: b Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) , Singapore , and.
authors: Yong Wah
authors: YW
authors: Tan
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Jianhe
authors: J
authors: Peng
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Thomas H
authors: TH
authors: Keller
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: Jeffrey
authors: J
authors: Hill
authors: b Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) , Singapore , and.|c Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology , National University of Singapore , Singapore.
authors: Justin J H
authors: JJ
authors: Chu
authors: a Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR) , Singapore .
authors: C S Brian
authors: CS
authors: Chia
mesh_terms: D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D029821:Enterovirus A, Human / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D007555:Isoxazoles; D057786:Peptidomimetics; D011480:Protease Inhibitors; D011760:Pyrrolidinones; D014764:Viral Proteins; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D014633:Valine; C118874:rupintrivir
keywords: 3C protease; EV71; Rupintrivir; peptide-based inhibitor