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Structure-guided design, synthesis and evaluation of macrocyclic and peptidomimetic inhibitors of viral proteases
Damalanka, Vishnu C.
Damalanka, Vishnu C.
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Dissertation
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2017-07
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Abstract
Human noroviruses are the primary cause of non-bacterial acute gastroenteritis
worldwide and are associated with high morbidity and a heavy economic burden. In the
U.S. alone noroviruses account for ~21 million cases, resulting in 70,000
hospitalizations and 800 deaths annually, and impact most severely the young and
elderly, and immunocompromised individuals. Combating norovirus infections presents
a challenge because of their high infectivity, ease of transmission, the dearth of
norovirus-specific therapeutics/prophylactics and vaccines, and a poor understanding of
norovirus pathophysiology.
Noroviruses are icosahedral, single-stranded, positive sense RNA viruses whose
genome (7-8 kb) is comprised of three open reading frames (ORFs) that encode a 200
kDa polyprotein (ORF1), a major capsid protein VP1 (ORF2) and a small basic protein
VP2 (ORF3). Following translation of the viral genome, the viral polyprotein is cleaved
by the viral-encoded 3C-like protease (NS6pro) to generate structural and nonstructural
proteins. NS6pro is essential for virus replication, consequently, it is an attractive target
for the discovery of anti-norovirus small molecule therapeutics.
Norovirus 3CL protease (NS6pro) is a cysteine protease with a Cys-His-Glu
catalytic triad, an extended binding site, and a chymotrypsin-like fold. The protease
displays a near absolute requirement for a P1 glutamine residue or equivalent. The
enzyme is an attractive target for the discovery and development of anti-norovirus
therapeutics and prophylactics. The dissertation describes for the first time the
structure-guided design of cell-permeable macrocyclic inhibitors of the protease, as well
as pertinent structural, biochemical, and cell-based studies.
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Thesis (Ph.D.)-- Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry
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Wichita State University
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Copyright 2017 by Vishnu Chakradhari Damalanka
All Rights Reserved