Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies

• DOI: 10.1016/j.ejmech.2016.04.013
• Publication Date: 2016-04-30T23:44:22Z
• Authors: Pathum M. Weerawarna; Yunjeong Kim; Anushka C. Galasi...; Vishnu C. Damalanka; Gerald H. Lushington; Kevin R. Alliston; Nurjahan Mehzabeen; Kevin P. Battaile; Scott Lovell; Kyeong-Ok Chang; William C. Groutas
• Keywords: Acute gastroenteritis; Triazole

Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies.