title: Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors.
abstract: Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED(50) of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
authors.forename: Sivakoteswara Rao
authors.initials: SR
authors.lastname: Mandadapu
authors.forename: Mallikarjuna Reddy
authors.initials: MR
authors.lastname: Gunnam
authors.forename: Kok-Chuan
authors.initials: KC
authors.lastname: Tiew
authors.forename: Roxanne Adeline Z
authors.initials: RA
authors.lastname: Uy
authors.forename: Allan M
authors.initials: AM
authors.lastname: Prior
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
authors.forename: Duy H
authors.initials: DH
authors.lastname: Hua
authors.forename: Yunjeong
authors.initials: Y
authors.lastname: Kim
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D029322:Norovirus / Q000201:enzymology*; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013447:Sulfites / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D013447:Sulfites; D014764:Viral Proteins; D010447:Peptide Hydrolases; C042345:hydrogen sulfite