Novel agmatine and agmatine-like peptidomimetic inhibitors of the West Nile virus NS2B/NS3 serine protease

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 mu M and was inactive against thrombin (IC50 > 100 mu M). 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. (C) 2011 Elsevier Masson SAS. All rights reserved.