title: Design, synthesis, and evaluation of 3C protease inhibitors as anti-enterovirus 71 agents.
abstract: Human enterovirus (EV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. A peptidomimetic inhibitor AG7088 was developed to inhibit the 3C protease of rhinovirus (a member of the family), a chymotrypsin-like protease required for viral replication, by forming a covalent bond with the active site Cys residue. In this study, we have prepared the recombinant 3C protease from EV71 (TW/2231/98), a particular strain which causes severe outbreaks in Asia, and developed inhibitors against the protease and the viral replication. For inhibitor design, the P3 group of AG7088, which is not interacting with the rhinovirus protease, was replaced with a series of cinnamoyl derivatives directly linked to P2 group through an amide bond to simplify the synthesis. While the replacement caused decreased potency, the activity can be largely improved by substituting the alpha,beta-unsaturated ester with an aldehyde at the P1' position. The best inhibitor 10b showed EC(50) of 18 nM without apparent toxicity (CC(50)>25 microM). Our study provides potent inhibitors of the EV71 3C protease as anti-EV71 agents and facilitates the combinatorial synthesis of derivatives for further improving the inhibitory activity.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Taipei 11529, Taiwan.
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Jiun-Jie
authors.initials: JJ
authors.lastname: Shie
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Guei-Rung
authors.initials: GR
authors.lastname: Yen
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Hun-Ge
authors.initials: HG
authors.lastname: Liu
authors.forename: Sung-Nain
authors.initials: SN
authors.lastname: Tseng
authors.forename: Shih-Cheng
authors.initials: SC
authors.lastname: Chang
authors.forename: Ching-Yin
authors.initials: CY
authors.lastname: Lee
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Liang
mesh_terms: D000086042:3C Viral Proteases; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015195:Drug Design; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases