Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors.
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.
Yin
Zheng
Z
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, 138670 Singapore. zheng.yin@novartis.com
Patel
Sejal J
SJ
Wang
Wei-Ling
WL
Chan
Wai-Ling
WL
Ranga Rao
K R
KR
Wang
Gang
G
Ngew
Xinyi
X
Patel
Viral
V
Beer
David
D
Knox
John E
JE
Ma
Ngai Ling
NL
Ehrhardt
Claus
C
Lim
Siew Pheng
SP
Vasudevan
Subhash G
SG
Keller
Thomas H
TH
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
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