The West Nile virus (WNV), a flavivirus, has rapidly spread throughout the United States and has been a global epidemic since the early 1990’s. The virus is spread to humans via infected mosquitoes blood meals. Severe WNV infections attack the central nervous system resulting in meningitis which can be fatal. Currently there are no approved therapeutic treatments for WNV infections, only the symptoms can be managed. A therapeutic target for WNV infections is the viral NS2B-NS3 protease, which is responsible for viral replication and assembly in infected host cells. Inhibition of the NS2B-NS3 protease has been reported to halt viral replication in cells, thereby ending the infection. The goal of this project is to identify small molecule inhibitors for the NS2B-NS3 protease. With the ultimate purpose of developing a viable therapeutic treatment for WNV infection.<br/>Short peptide sequences, with basic residues such as arginine and lysine, have been shown to inhibit the NS2B-NS3 protease with high potency. However, peptides have poor bioavailability, due to amide bonds that readily undergo hydrolysis in the body. Peptidomimetics are small molecules that mimic peptide interactions, but do not have the peptide backbone that can be easily hydrolyzed. We report the synthesis of a library of peptidomimetics, featuring guanidine, and evaluated the library for inhibition of the NS2B-NS3 protease, via competitive FRET-based protease assay. Solid phase synthesis was performed to couple on diverse structures that mimic a peptide and it’s side chains. The screen resulted in several novel peptidomimetic inhibitors for the NS2B-NS3 protease. These guanidine peptidomimetic molecules were measured to inhibit the WNV protease by 40% at a concentration of 60 µM. The guanidine scaffold has been synthetically explored to produce a novel 2<sup>nd</sup> generation library to optimize the number and position of guanidine groups on the lead scaffold.

Novel peptidomimetic inhibitors for the West Nile virus NS2B-NS3 protease

251st National Meeting (2016)

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