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

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)300-318
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Volume119
DOIs
StatePublished - 2016

Keywords

  • 3CL protease
  • Macrocyclic inhibitors
  • Norovirus
  • β-strand conformation

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