title: Peptide inhibitors of West Nile NS3 protease: SAR study of tetrapeptide aldehyde inhibitors.
abstract: A series of inhibitors related to the benzoyl-norleucine-lysine-arginine-arginine (Bz-nKRR) tetrapeptide aldehyde was synthesized. When evaluated against the West Nile virus (WNV) NS3 protease, the measured IC(50) ranges from approximately 1 to 200 microM. Concurrently, a modeling study using the recently published crystal structure of the West Nile NS3/NS2B protease complex (pdb code 2FP7) was conducted. We found that the crystal structure is relevant in explaining the observed SAR for this series of tetrapeptides, with the S1 and S2 pockets being the key peptide recognition sites. In general, a residue capable of both pi-stacking and hydrogen bonding is favored in the S1 pocket, while a positively charged residue is preferred in the S2 pocket. This study not only confirms the importance of the NS2B domain in substrate-based inhibitor binding of WNV, it also suggests that the crystal structure would provide useful guidance in the drug discovery process of related Flavivirus proteases, given the high degree of homology.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670 Singapore.
authors.forename: John E
authors.initials: JE
authors.lastname: Knox
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Sejal J
authors.initials: SJ
authors.lastname: Patel
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Wang
authors.forename: Wai-Ling
authors.initials: WL
authors.lastname: Chan
authors.forename: K R
authors.initials: KR
authors.lastname: Ranga Rao
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Xinyi
authors.initials: X
authors.lastname: Ngew
authors.forename: Viral
authors.initials: V
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D000447:Aldehydes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014902:West Nile virus / Q000201:enzymology*
chemical_list: D000447:Aldehydes; D009842:Oligopeptides; D011480:Protease Inhibitors; C515237:benzoyl-norleucyl-lysyl-arginyl-arginal; D012697:Serine Endopeptidases