title: Novel agmatine and agmatine-like peptidomimetic inhibitors of the West Nile virus NS2B/NS3 serine protease.
abstract: This communication reports the synthesis and inhibitory activities of novel non-covalent peptidomimetic inhibitors of the West Nile virus NS2B/NS3 protease containing a decarboxylated P1 arginine (agmatine; 4-aminobutylguanidine) and related analogues. One agmatine peptidomimetic (4-phenyl-phenacetyl-Lys-Lys-agmatine; compound 2) was shown to be a competitive inhibitor with a binding affinity of K(i) 2.05 ± 0.13 μM and was inactive against thrombin (IC(50) > 100 μM). Our results suggest that peptidomimetics with agmatine at the P1 position could potentially be employed as starting tools in the design of non-covalent competitive protease inhibitors due to their relative stability and ease of chemical synthesis compared to inhibitors containing reactive electrophilic warheads.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research (A STAR), 31 Biopolis Way, Nanos #03-01, Singapore 138669, Singapore.
authors.forename: Huichang Annie
authors.initials: HA
authors.lastname: Lim
authors.forename: Joma
authors.initials: J
authors.lastname: Joy
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: Cheng
authors.initials: C
authors.lastname: San Brian Chia
mesh_terms: D000376:Agmatine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D006801:Humans; D007700:Kinetics; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014902:West Nile virus / Q000737:chemistry / Q000201:enzymology; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000376:Agmatine; D000998:Antiviral Agents; D057786:Peptidomimetics; D011480:Protease Inhibitors; D020365:RNA Helicases; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D013917:Thrombin; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases