Potent cationic inhibitors of West Nile virus NS2B/NS3 protease with serum stability, cell permeability and antiviral activity.
West Nile virus (WNV) has spread rapidly around the globe, efficiently crossing species from migrating birds into humans and other mammals. The viral protease NS2B-NS3 is important for WNV replication and recognizes dibasic substrate sequences common to other flaviviral proteases but different from most mammalian proteases. Potent inhibitors of WNV protease with antiviral activity have been elusive to date. We report the smallest and most potent inhibitors known for this enzyme, cationic tripeptides with nonpeptidic caps at the N-terminus and aldehyde at the C-terminus. One of these, compound 3 ( Ki = 9 nM) is stable in serum (>90% intact after 3 h, 37 degrees C), cell permeable, and shows antiviral activity (IC 50 1.6 microM) without cytotoxicity (IC 50 >400 microM), thereby validating the approach of inhibiting WNV protease to suppress WNV replication.
Stoermer
Martin J
MJ
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Chappell
Keith J
KJ
Liebscher
Susann
S
Jensen
Christina M
CM
Gan
Chun H
CH
Gupta
Praveer K
PK
Xu
Wei-Jun
WJ
Young
Paul R
PR
Fairlie
David P
DP
D000998:Antiviral Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002412:Cations; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases