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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Mandadapu, Sivakoteswara Rao¹  Gunnam, Mallikarjuna Reddy¹  Tiew, Kok-Chuan¹  Uy, Roxanne Adeline Z.¹  Prior, Allan M.²  Alliston, Kevin R.¹  Hua, Duy H.²  Kim, Yunjeong³  Chang, Kyeong-Ok³  Groutas, William C.¹ 

[1] Wichita State Univ, Dept Chem, Wichita, KS 67260 USA

[2] Kansas State Univ, Dept Chem, Manhattan, KS 66506 USA

[3] Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA

关键词: Norovirus 3CL protease;    Bisulfite salt adducts;    Transition state inhibitors;   

DOI  :  10.1016/j.bmcl.2012.11.026

来源: Elsevier

【 摘 要 】

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 alpha-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 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 alpha-ketoheterocycles and alpha-ketoesters. (C) 2012 Elsevier Ltd. All rights reserved.

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