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

Vishnu C. Damalanka, Yunjeong Kim, Anushka C. Galasiti Kankanamalage, Athri D. Rathnayake, Nurjahan Mehzabeen, Kevin P. Battaile, Scott Lovell, Harry Nhat Nguyen, Gerald H. Lushington, Kyeong Ok Chang, William C. Groutas

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 anti-norovirus 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.

Original languageEnglish
Pages (from-to)881-890
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume143
DOIs
StatePublished - Jan 1 2018

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