The West Nile virus (WNV) is a member of the Flaviviridae family of viruses transmitted by infected mosquitoes.1 Originating from Africa, it has spread to humans in Asia, southern Europe, the Middle East and North America.2 Between 1999 and 2011, the United States Center for Disease Control reported more than 23,000 human infections in North America, resulting in 1,251 fatalities.3 The most recent outbreak that occurred in North America resulted in 1,118 human infections and 41 fatalities in 2012.4 There is currently no vaccine or specific drug therapy to treat WNV infections, highlighting the urgent need to develop an anti-viral against this disease.
A potential drug target is the viral NS2B-NS3 trypsin-like serine protease due to its crucial role in viral replication.5 Herein, we describe the structure-activity relationships of dipeptides containing a C-terminal agmatine (decarboxylated arginine) moiety which were found to inhibit the viral protease at low micromolar IC50s.6,7 We believe our results will facilitate the design of new peptide-based anti-virals against WNV infections.