Development of anti-coxsackievirus agents targeting 3C protease.
Peptidomimetic anti-viral agents against Coxsackievirus B3 (CVB3) were developed using a strategy involving the inhibition of 3C protease (CVB3 3C(pro)), a target for CVB3-mediated myocarditis or pericarditis. In an attempt to improve the inhibitory activity against CVB3, a variety of hetero-aromatic groups were incorporated into the α,β-unsaturated ester as Michael acceptor moiety, which is the position of interaction with the cysteine moiety in the P1' active site of CVB3 3C(pro). Among these hetero-aromatic groups, the quinoline analogs 9c and 9e, with IC(50) values of 250 and 130 nM as determined from an enzyme assay, significantly inhibited the CVB3-mediated cell cytotoxicity, indicating parallel anti-viral activities. A comparison of the binding modes of the potent inhibitor 9e and the relatively weak inhibitor 9n was explored in a molecular docking study, which revealed that compound 9n lacked hydrogen bonds in its interactions with Gly129, 128, and 145.
School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Republic of Korea.
Bo-Kyoung
BK
Kim
Jeong-Hyun
JH
Kim
Na-Ri
NR
Kim
Won-Gil
WG
Lee
So-Deok
SD
Lee
Soo-Hyeon
SH
Yun
Eun-Seok
ES
Jeon
Yong-Chul
YC
Kim
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004770:Enterovirus / Q000201:enzymology*; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; D011804:Quinolines; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases