Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

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Issue Date
2018-01-01
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Authors
Damalanka, Vishnu C.
Kim, Yunjeong
Kankanamalage, Anushka C. Galasiti
Rathnayake, Athri D.
Mehzabeen, Nurjahan
Battaile, Kevin P.
Lovell, Scott
Nguyen, Harry Nhat
Lushington, Gerald H.
Chang, Kyeong-Ok
Advisor
Citation

Damalanka, Vishnu C.; Kim, Yunjeong; Kankanamalage, Anushka C. Galasiti; Rathnayake, Athri D.; Mehzabeen, Nurjahan; Battaile, Kevin P.; Lovell, Scott; Nguyen, Harry Nhat; Lushington, Gerald H.; Chang, Kyeong-Ok; Groutas, William C. 2018. Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease. European Journal of Medicinal Chemistry, vol. 143:pp 881-890

Abstract

Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display ant-inorovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.

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