The West Nile virus (WNV) is a neurovirulent mosquito borne pathogen that is prevalent worldwide. Upon infection, the viral genome is translated by host ribosomes into a genomic polyprotein containing all protein elements necessary for viral replication. The genomic polyprotein is cleaved by the viral NS2B-NS3 protease. The NS2B is a cofactor that binds to the NS3 to provide the proteolytic activity needed for viral replication. The protease is an integral component of the WNV life cycle and therefore an attractive therapeutic target for WNV infection. Zafirlukast, an FDA approved Asthma alleviant has been discovered as a novel allosteric inhibitor for the NS2B-NS3 protease. Zafirlukast has shown promising inhibition against the NS2B-NS3 protease through disruption of the NS2B cofactor binding to the NS3 to form the active protease with an IC50 value of 32 µM. The Zafirlukast scaffold consists of three components: a cyclopental carbamate, an o-toluic sulfonamide, and a methylated indole core. This research explores the synthesis of third-generation Zafirlukast derivatives by creating analogs of the indole core. Altering the indole core modifies the angle and position of the phenyl carbamate and o-toluic sulfonamide within the allosteric site which would increase binding and inhibition. The third-generation molecules contained variations in the core by substituting it with quinolines, phthalimides, and triazoles. These core analog structures will be evaluated in an enzymatic assay to probe the allosteric binding site and lead to improved NS2B-NS3 protease inhibition. These third-generation compounds will expand our knowledge of the NS2B-NS3 protease inhibitor molecular scaffold.

Exploring Zafirlukast as a novel West Nile virus NS2B-NS3 protease inhibitor

2019 Fall National Meeting

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