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Structure-based design and optimization of dipeptidyl inhibitors of norovirus 3CL protease
Uy, Roxanne Adeline Z.
Uy, Roxanne Adeline Z.
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thesis
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2014-07
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Electronic dissertations
Electronic dissertations
Electronic dissertations
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Abstract
Noroviruses are the primary cause of acute gastroenteritis. They are associated
with increased hospitalization and mortality among the elderly and
immunocompromised patients. In developing countries, noroviruses are linked to
significant mortality (200,000) in children < 5 years old. Importantly, norovirus infection
poses a high bioterrorism threat, and the problem is further compounded by the current
dearth of effective vaccines or norovirus-specific antivirals.
The studies described in this thesis lay the groundwork for the discovery and
development of small molecule therapeutics for the treatment and prophylaxis of
norovirus infection. Specifically, these studies have as their primary focus the structurebased
design and optimization of a dipeptidyl series of inhibitors of norovirus 3CL
protease, an enzyme shown to be essential for replication of the virus and a validated
target for the development of anti-norovirus therapeutics. The studies described herein
include the synthesis and in vitro biochemical evaluation of dipeptidyl transition state
inhibitors and transition state mimics of 3CL protease. The selectivity of the inhibitors,
as well as the anti-norovirus activity of the synthesized compounds in a cell-based
replicon system was also evaluated..
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Thesis (M.S.)--Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry
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Wichita State University
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Copyright 2014 Roxanne Adeline Z. Uy