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 Ki 2.05 ± 0.13 μM and was inactive against thrombin (IC50 > 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.

Ten novel peptidomimetics containing agmatine were assayed against the West Nile virus NS2B/NS3 protease. The most potent inhibitor, Compound 2, displayed a binding affinity of Ki 2.05 ± 0.13 μM.Figure optionsDownload as PowerPoint slideHighlights
► The West Nile virus NS2B/NS3 protease is a trypsin-like serine protease.
► Ten novel peptidomimetics containing agmatine and analogues were synthesized.
► Compound 2 was a competitive inhibitor with a binding affinity of Ki 2.05 μM
► Such peptidomimetics can be used to design novel trypsin-like protease inhibitors.