title: Discovery, synthesis, and in vitro evaluation of West Nile virus protease inhibitors based on the 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold.
abstract: West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B-NS3 protease inhibitor with a 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold was identified by screening a small library of non-peptidic compounds. This initial hit was optimized by solution-phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor (1a40, IC(50) = 5.41±0.45 μM) of WNV NS2B-NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the S enantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)-1a40 is a preferred isomer for inhibition of WNV NS3 protease.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Samanta
authors.forename: Taian
authors.initials: T
authors.lastname: Cui
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D011480:Protease Inhibitors