Novel agmatine dipeptide inhibitors against the West Nile virus NS2B/NS3 protease: a P3 and N-cap optimization study.
This communication describes the synthesis and inhibitory activities of thirty-seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease. Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC50 2.6 ± 0.3 μM) with improved inhibitory activity in comparison to the most potent inhibitor described in our recent report [IC50 4.7 ± 1.2 μM; Lim et al., Eur. J. Med. Chem. 46 (2011) 3130-3134]. In addition, our study cleared the contention surrounding the previous X-ray co-crystallization study and an enzyme inhibition report on the binding conformation adopted by active-site peptide aldehydes. Our data should provide valuable insights into the design of future peptidomimetic antivirals against WNV infections.
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A STAR), 31 Biopolis Way, Nanos #03-01, Singapore 138669, Singapore.
Huichang Annie
HA
Lim
Melgious Jin Yan
MJ
Ang
Joma
J
Joy
Anders
A
Poulsen
Wenshi
W
Wu
Shi Chie
SC
Ching
Jeffrey
J
Hill
Cheng San Brian
CS
Chia
D000376:Agmatine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020365:RNA Helicases / Q000187:drug effects; D012697:Serine Endopeptidases / Q000187:drug effects; D012984:Software; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000376:Agmatine; D004151:Dipeptides; 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