title: Antiviral activities of peptide-based covalent inhibitors of the Enterovirus 71 3C protease.
abstract: Hand, Foot and Mouth Disease is a highly contagious disease caused by a range of human enteroviruses. Outbreaks occur regularly, especially in the Asia-Pacific region, putting a burden on public healthcare systems. Currently, there is no antiviral for treating this infectious disease and the only vaccines are limited to circulation in China, presenting an unmet medical need that needs to be filled urgently. The human enterovirus 3 C protease has been deemed a plausible drug target due to its essential roles in viral replication. In this study, we designed and synthesized 10 analogues of the Rhinovirus 3 C protease inhibitor, Rupintrivir, and tested their 3 C protease inhibitory activities followed by a cellular assay using human enterovirus 71 (EV71)-infected human RD cells. Our results revealed that a peptide-based compound containing a trifluoromethyl moiety to be the most potent analogue, with an EC50 of 65 nM, suggesting its potential as a lead for antiviral drug discovery.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, 138673, Singapore.
authors.forename: Yong Wah
authors.initials: YW
authors.lastname: Tan
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Melgious Jin Yan
authors.initials: MJ
authors.lastname: Ang
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Qiu Ying
authors.initials: QY
authors.lastname: Lau
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Fui Mee
authors.initials: FM
authors.lastname: Ng
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Siew Wen
authors.initials: SW
authors.lastname: Then
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Peng
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, 138673, Singapore.
authors.forename: Wan Jin
authors.initials: WJ
authors.lastname: Hong
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, 138669, Singapore.
authors.forename: Cheng San Brian
authors.initials: CS
authors.lastname: Chia
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos #06-05, 138673, Singapore.|Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, National University Health System, National University of Singapore 117597, Singapore.
authors.forename: Justin Jang Hann
authors.initials: JJ
authors.lastname: Chu
mesh_terms: D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003546:Cysteine Endopeptidases; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004770:Enterovirus / Q000187:drug effects; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases