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The problem is further compounded by the current lack of norovirus\u2010specific antivirals or vaccines. Noroviruses have a single\u2010stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus\u2010encoded 3C\u2010like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication, consequently, NV 3CLpro has emerged as an attractive target for the discovery of norovirus therapeutics and prophylactics. We have recently described the structure\u2010based design of macrocyclic transition state inhibitors of NV 3CLpro. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors were synthesized and high resolution cocrystal structures determined. The results of our studies tentatively suggest that the macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross\u2010talk between the S<jats:sub>2<\/jats:sub> and S<jats:sub>4<\/jats:sub> subsites.<\/jats:p>","DOI":"10.1002\/prot.25682","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T23:32:55Z","timestamp":1552951975000},"page":"579-587","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease"],"prefix":"10.1002","volume":"87","author":[{"given":"Anushka C.","family":"Galasiti Kankanamalage","sequence":"first","affiliation":[{"name":"Department of Chemistry Wichita State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pathum M.","family":"Weerawarna","sequence":"additional","affiliation":[{"name":"Department of Chemistry Wichita State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athri D.","family":"Rathnayake","sequence":"additional","affiliation":[{"name":"Department of Chemistry Wichita State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Medicine &amp; Pathobiology College of Veterinary Medicine, Kansas State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurjahan","family":"Mehzabeen","sequence":"additional","affiliation":[{"name":"Protein Structure Laboratory The University of Kansas  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Battaile","sequence":"additional","affiliation":[{"name":"IMCA\u2010CAT, Hauptman\u2010Woodward Medical Research Institute APS Argonne National Laboratory  Argonne Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Lovell","sequence":"additional","affiliation":[{"name":"Protein Structure Laboratory The University of Kansas  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong\u2010Ok","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Medicine &amp; Pathobiology College of Veterinary Medicine, Kansas State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5248-7912","authenticated-orcid":false,"given":"William C.","family":"Groutas","sequence":"additional","affiliation":[{"name":"Department of Chemistry Wichita State University  Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"61","article-title":"Noroviruses: the leading cause of gastroenteritis worldwide","volume":"10","author":"Koo HL","year":"2010","journal-title":"Discov Med"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid1908.130465"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.130426"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00075-14"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1207742"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072788"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151219"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12722"},{"key":"e_1_2_7_10_1","unstructured":"National Institutes of Health\/U.S.National Library of Medicine\/Medline Plus. 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