Peptide inhibitors of Dengue virus NS3 protease. Part 1: Warhead.
Substrate-based tetrapeptide inhibitors with various warheads were designed, synthesized, and evaluated against the Dengue virus NS3 protease. Effective inhibition was achieved by peptide inhibitors with electrophilic warheads such as aldehyde, trifluoromethyl ketone, and boronic acid. A boronic acid has the highest affinity, exhibiting a K(i) of 43 nM.
Yin
Zheng
Z
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore. zheng.yin@novartis.com
Patel
Sejal J
SJ
Wang
Wei-Ling
WL
Wang
Gang
G
Chan
Wai-Ling
WL
Rao
K R Ranga
KR
Alam
Jenefer
J
Jeyaraj
Duraiswamy A
DA
Ngew
Xinyi
X
Patel
Viral
V
Beer
David
D
Lim
Siew Pheng
SP
Vasudevan
Subhash G
SG
Keller
Thomas H
TH
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; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; 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
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