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Date of Award
Biochemistry and Molecular Biology
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
Medapureddy, Prasanna Rama Lakshmi, "Chikungunya Virus Protease Structural Studies And Drug Design" (2017). Wayne State University Theses. 631.