title: Synthesis and in vitro evaluation of West Nile virus protease inhibitors based on the 2-{6-[2-(5-phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold.
abstract: In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1 a24, IC50 =3.4±0.2 μM) of the WNV NS2B-NS3 protease. Molecular docking of 1 a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.
authors.affiliation: Department of Chemistry, National University of Singapore, Singapore.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Samanta
authors.forename: Ting Liang
authors.initials: TL
authors.lastname: Lim
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013864:Thioglycolates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D052160:Benzothiazoles; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D013864:Thioglycolates; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases