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.

Thirty-seven novel agmatine dipeptides with various P3 and P4 groups were assayed against the West Nile virus NS2B/NS3 protease. The most potent inhibitor, compound 33, displayed an IC50 of 2.6 ± 0.3 μM, a two-fold improvement over a similar inhibitor described previously [Lim et al., Eur. J. Med. Chem. 46 (2011) 3130–3134]. Our results also shed light on the binding conformation adopted by similar active-site peptidomimetics.Figure optionsDownload as PowerPoint slideHighlights
► The West Nile virus recently caused an outbreak in USA with >40 fatalities.
► Its NS2B/NS3 serine protease is deemed to be a potential drug target.
► 37 novel agmatine dipeptides were synthesized and assayed for inhibitory activity.
► The most potent inhibitor displayed and IC50 of 2.6 μM.
►  Such peptidomimetics are useful starting points in the design of new antivirals.