Discovery of small molecule inhibitors for the West Nile Virus NS2B-NS3 protease
Mentor:Nicholas Salzameda, Associate Professor of Chemistry, California State University Of Fullerton
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 transmitted from infected mosquitoes taking a blood meal from humans. Severe WNV infections attack the central nervous system resulting in meningitis and 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 halts viral replication in cells, thereby ending the infection. The goal of this project is to identify small molecule inhibitors for the NS2B-NS3 protease. We will utilize a novel substrate activity screen approach to identify inhibitors. Small molecules will be coupled to a reporter group and incubated with the NS2B-NS3 protease and monitored for cleavage of the reporter group. Compounds that are cleaved by the NS2B-NS3 protease are considered NS2B-NS3 protease binders. These compounds will be converted into inhibitors by chemically removing the reporter group and replacing it with a non-cleavable group to produce a potent inhibitor for the NS2B-NS3 protease. We have synthesized the reporter molecule, 7-N-(fluorenylmethoxycarbonyl) aminocoumarin-4-acetic acid. The synthesis of the coumarin begins with 3-aminophenol and involved 6 chemical steps to give 7-N-(fluorenylmethoxycarbonyl) aminocoumarin-4-acetic acid as the final product. The coumarin will be coupled to each member of the chemical library using solid phase synthesis. Once the library is complete we will screen the library for novel NS2B-NS3 protease inhibitors.