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Access Type

WSU Access

Date of Award

January 2017

Degree Type

Thesis

Degree Name

M.S.

Department

Biochemistry and Molecular Biology

First Advisor

Ladislau Kovari

Abstract

According to Pan American Health Organization statistics, from 2013 more than 1.7 million cases of

CHIKV infections have been identified from all over the 45 countries of Americas. In 2015, CHIKV

infection joined the list of “nationally notifiable condition”. There is no FDA approved anti-CHIKV drug

till date. nsp2 protease plays a role in replication of CHIKV in the host cell and nsp2 is considered as one

of the potential anti-CHIKV drug target. Several experimental non peptidomimetics such as aryl alkylidene

and Quinazolinone derivatives and peptidomimetics against CHIKVpro have been studied. Using

computational techniques, we have shown that binding site of CHIKVpro is druggable and also analyzed

for important ligand-protein interactions. This study shows that substrate can influence the dynamics of

binding site region of protease by lowering its flexibility. In addition, computational aided drug design

techniques allowed us to design covalent peptidomimetics with improved cell permeability. We also report

here a successful optimization, expression and purification of CHIKVpro and performed enzyme

characterization experiments using FRET-based assays to validate the CHIKVpro activity. Future

directions include design of anti-CHIKV compounds with improved binding affinity and better

pharmacokinetics properties.

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