{"id":{"repo_id":"wichita-thes","oai_identifier":"oai:soar.wichita.edu:10057/14540"},"canonical_url":"https://search.dev.ndltd.org/etd/wichita-thes/oai:soar.wichita.edu:10057/14540","repository":{"repo_id":"wichita-thes","name":"Wichita State University","base_url":"https://soar.wichita.edu/oai/request"},"display":{"title":"Structure-guided design, synthesis and evaluation of macrocyclic and peptidomimetic inhibitors of viral proteases","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Damalanka, Vishnu C."],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-07","date_published":"2017-07","updated_at":"2026-07-24T06:06:46Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10057/14540"],"render_values":[{"text":"hdl:10057/14540","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2017-07"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10057/14540"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.other","label":"Dc Description Other","values":["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."]},{"key":"dc:title","label":"Title","values":["Structure-guided design, synthesis and evaluation of macrocyclic and peptidomimetic inhibitors of viral proteases"]}]}],"canonical_facts":{"dc:date.issued":["2017-07"],"dc:description.other":["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."],"dc:identifier":["hdl:10057/14540"],"dc:title":["Structure-guided design, synthesis and evaluation of macrocyclic and peptidomimetic inhibitors of viral proteases"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T06:06:46Z"}