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dc.contributor.advisorGroutas, William C.
dc.contributor.authorDamalanka, Vishnu C.
dc.date.accessioned2018-02-05T21:47:57Z
dc.date.available2018-02-05T21:47:57Z
dc.date.issued2017-07
dc.identifier.otherd17024s
dc.identifier.urihttp://hdl.handle.net/10057/14540
dc.descriptionThesis (Ph.D.)-- Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry
dc.description.abstractHuman 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.
dc.format.extentxix, 203 pages
dc.language.isoen_US
dc.publisherWichita State University
dc.rightsCopyright 2017 by Vishnu Chakradhari Damalanka All Rights Reserved
dc.subject.lcshElectronic dissertation
dc.titleStructure-guided design, synthesis and evaluation of macrocyclic and peptidomimetic inhibitors of viral proteases
dc.typeDissertation


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