title: Development of potent inhibitors of the coxsackievirus 3C protease.
abstract: Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2' pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2' position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2' pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Eui Seung
authors.initials: ES
authors.lastname: Lee
authors.forename: Won Gil
authors.initials: WG
authors.lastname: Lee
authors.forename: Soo-Hyeon
authors.initials: SH
authors.lastname: Yun
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Rho
authors.forename: Isak
authors.initials: I
authors.lastname: Im
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Yang
authors.forename: Saravanan
authors.initials: S
authors.lastname: Sellamuthu
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sun Jae
authors.initials: SJ
authors.lastname: Kwon
authors.forename: Ohkmae K
authors.initials: OK
authors.lastname: Park
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Jeon
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000086042:3C Viral Proteases; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases; D004770:Enterovirus / Q000187:drug effects* / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012229:Rhinovirus / Q000201:enzymology; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D007555:Isoxazoles; D011760:Pyrrolidinones; D014764:Viral Proteins; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D014633:Valine; C118874:rupintrivir