Oxadiazole-based cell permeable macrocyclic transition state inhibitors of norovirus 3CL protease

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Damalanka, Vishnu C.
Kim, Yunjeong
Alliston, Kevin R.
Weerawarna, Pathum M.
Kankanamalage, Anushka C. Galasiti
Lushington, Gerald H.
Mehzabeen, Nurjahan
Battaile, Kevin P.
Lovell, Scott
Chang, Kyeong-Ok

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, and William C. Groutas. Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease. Journal of Medicinal Chemistry 2016 59 (5), 1899-1913


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.

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