Presentation Title

Synthesizing Zafirlukast Analogs as a Novel Allosteric West Nile Virus NS2B-NS3 Protease Inhibitor

Faculty Mentor

Dr. Nicholas T. Salzameda

Start Date

17-11-2018 12:30 PM

End Date

17-11-2018 2:30 PM

Location

CREVELING 3

Session

POSTER 2

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

The West Nile Virus (WNV) is a neurovirulent mosquito borne pathogen that is prevalent in humans worldwide. Upon infection, the viral genome is translated by host ribosomes into a genomic polyprotein: a single molecule containing all proteins necessary for viral replication. The NS2B protein binds into a shallow cleft near the active site of the NS3 protein, which gives the complex proteolytic activity. This cleft can be exploited as a site for allosteric inhibition by preventing the binding of the NS2B to the NS3 protein, thus terminating enzymatic activity of the protease and halting the production of new viral particles. Therefore, the protease is an integral component of the WNV and is an attractive therapeutic target. This research focuses on probing the core scaffold of Zafirlukast; an FDA approved treatment for Asthma, as a novel NS2B-NS3 protease inhibitor. Zafirlukast has shown promising inhibition against the NS2B-NS3 protease with an IC50 value of 32 µM. It is believed Zafirlukast occupies the allosteric site on the NS3 protein and prevents the NS2B cofactor from binding. The Zafirlukast scaffold consists of three major components: a cyclopental carbamate, an o-toluic sulfonamide, and a methylated indole core. This research explores the synthesis of third-generation Zafirlukast derivatives by altering the indole core. Substituting the indole with other heterocycles will affect the angle and position of the phenyl carbamate and o-toluic sulfonamide within the allosteric site which could increase binding. Our third-generation molecules contained variations in the core by substituting it with privileged scaffolds such as quinolines, phthalimides, and triazoles. These core analog structures will probe the allosteric site and lead to improved binding of the NS2B-NS3 protease. These third-generation compounds will expand our knowledge of the NS2B-NS3 protease inhibitor molecular scaffold.

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Nov 17th, 12:30 PM Nov 17th, 2:30 PM

Synthesizing Zafirlukast Analogs as a Novel Allosteric West Nile Virus NS2B-NS3 Protease Inhibitor

CREVELING 3

The West Nile Virus (WNV) is a neurovirulent mosquito borne pathogen that is prevalent in humans worldwide. Upon infection, the viral genome is translated by host ribosomes into a genomic polyprotein: a single molecule containing all proteins necessary for viral replication. The NS2B protein binds into a shallow cleft near the active site of the NS3 protein, which gives the complex proteolytic activity. This cleft can be exploited as a site for allosteric inhibition by preventing the binding of the NS2B to the NS3 protein, thus terminating enzymatic activity of the protease and halting the production of new viral particles. Therefore, the protease is an integral component of the WNV and is an attractive therapeutic target. This research focuses on probing the core scaffold of Zafirlukast; an FDA approved treatment for Asthma, as a novel NS2B-NS3 protease inhibitor. Zafirlukast has shown promising inhibition against the NS2B-NS3 protease with an IC50 value of 32 µM. It is believed Zafirlukast occupies the allosteric site on the NS3 protein and prevents the NS2B cofactor from binding. The Zafirlukast scaffold consists of three major components: a cyclopental carbamate, an o-toluic sulfonamide, and a methylated indole core. This research explores the synthesis of third-generation Zafirlukast derivatives by altering the indole core. Substituting the indole with other heterocycles will affect the angle and position of the phenyl carbamate and o-toluic sulfonamide within the allosteric site which could increase binding. Our third-generation molecules contained variations in the core by substituting it with privileged scaffolds such as quinolines, phthalimides, and triazoles. These core analog structures will probe the allosteric site and lead to improved binding of the NS2B-NS3 protease. These third-generation compounds will expand our knowledge of the NS2B-NS3 protease inhibitor molecular scaffold.