Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors.

Autor: Mandadapu SR; Department of Chemistry, Wichita State University, Wichita, KS 67260, USA., Gunnam MR, Tiew KC, Uy RA, Prior AM, Alliston KR, Hua DH, Kim Y, Chang KO, Groutas WC
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Jan 01; Vol. 23 (1), pp. 62-5. Date of Electronic Publication: 2012 Nov 21.
DOI: 10.1016/j.bmcl.2012.11.026
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: