title: Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases.
abstract: A series of 45 peptide inhibitors was designed, synthesized, and evaluated against the NS2B-NS3 proteases of the four subtypes of dengue virus, DEN-1-4. The design was based on proteochemometric models for Michaelis (Km) and cleavage rate constants (kcat) of protease substrates. This led first to octapeptides showing submicromolar or low micromolar inhibitory activities on the four proteases. Stepwise removal of cationic substrate non-prime side residues and variations in the prime side sequence resulted finally in an uncharged tetrapeptide, WYCW-NH2, with inhibitory Ki values of 4.2, 4.8, 24.4, and 11.2 μM for the DEN-1-4 proteases, respectively. Analysis of the inhibition data by proteochemometric modeling suggested the possibility for different binding poses of the shortened peptides compared to the octapeptides, which was supported by results of docking of WYCW-NH2 into the X-ray structure of DEN-3 protease.
authors.affiliation: Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala University, 75124 Uppsala, Sweden.
authors.forename: Peteris
authors.initials: P
authors.lastname: Prusis
authors.forename: Muhammad
authors.initials: M
authors.lastname: Junaid
authors.forename: Ramona
authors.initials: R
authors.lastname: Petrovska
authors.forename: Sviatlana
authors.initials: S
authors.lastname: Yahorava
authors.forename: Aleh
authors.initials: A
authors.lastname: Yahorau
authors.forename: Gerd
authors.initials: G
authors.lastname: Katzenmeier
authors.forename: Maris
authors.initials: M
authors.lastname: Lapins
authors.forename: Jarl E S
authors.initials: JE
authors.lastname: Wikberg
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000085242:Viral Proteases
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D014764:Viral Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases