title: Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors.
abstract: With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K(i)=5.8 microM). In general, we observe that interactions of P(2) side chain are more important than P(1) followed by P(3) and P(4). Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P(1) Arg is identified.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, 138670 Singapore. zheng.yin@novartis.com
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: John E
authors.initials: JE
authors.lastname: Knox
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.forename: Claus
authors.initials: C
authors.lastname: Ehrhardt
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*; D001667:Binding, Competitive; D001897:Boronic Acids / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003716:Dengue Virus / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006860:Hydrogen Bonding; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000447:Aldehydes; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D007659:Ketones; D010455:Peptides; D011480:Protease Inhibitors; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases