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

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.

SUBMITTER: Damalanka VC

PROVIDER: S-EPMC5737831 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Damalanka Vishnu C VC Kim Yunjeong Y Galasiti Kankanamalage Anushka C AC Rathnayake Athri D AD Mehzabeen Nurjahan N Battaile Kevin P KP Lovell Scott S Nguyen Harry Nhat HN Lushington Gerald H GH Chang Kyeong-Ok KO Groutas William C WC

European journal of medicinal chemistry 20171206

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 di ...[more]

PMID: 29227928

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