Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

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• 作者：Vishnu C. Damalanka ; Yunjeong Kim ; Kevin R. Alliston ; Pathum M. Weerawarna ; Anushka C. Galasiti Kankanamalage ; Gerald H. Lushington ; Nurjahan Mehzabeen ; Kevin P. Battaile ; Scott Lovell ; Kyeong-Ok Chang ; William C. Groutas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1899-1913
• 全文大小：573K
• ISSN：1520-4804

文摘

Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.