Structural and inhibitor studies of norovirus 3C-like proteases

Daisuke Takahashi, Yunjeong Kim, Scott Lovell, Om Prakash, William C. Groutas, Kyeong Ok Chang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Noroviruses have a single-stranded, positive sense 7-8. kb RNA genome, which encodes a polyprotein precursor processed by a virus-encoded 3C-like cysteine protease (3CLpro) to generate mature non-structural proteins. Because processing of the polyprotein is essential for virus replication, norovirus 3CLpro has been targeted for the discovery of anti-norovirus small molecule therapeutics. Thus, we performed functional, structural and inhibition studies of norovirus 3CLpro with fluorescence resonance energy transfer (FRET) assay, X-ray crystallography, and NMR spectroscopy with a synthetic protease inhibitor. Three 3CLpro from Norwalk virus (NV, genogroup I), MD145 (genogroup II) and murine norovirus-1 (MNV-1, genogroup V) were optimized for a FRET assay, and compared for the inhibitory activities of a synthetic protease inhibitor (GC376). The apo 3D structures of NV 3CLpro determined with X-ray crystallography and NMR spectroscopy were further analyzed. In addition, the binding mode of NV 3CLpro-GC376 was compared with X-ray crystallography and NMR spectroscopy. The results of this report provide insight into the interaction of NV 3CLpro with substrate/inhibitor for better understanding of the enzyme and antiviral drug development.

Original languageEnglish
Pages (from-to)437-444
Number of pages8
JournalVirus Research
Volume178
Issue number2
DOIs
Publication statusPublished - Dec 26 2013

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Virology
  • Infectious Diseases

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    Takahashi, D., Kim, Y., Lovell, S., Prakash, O., Groutas, W. C., & Chang, K. O. (2013). Structural and inhibitor studies of norovirus 3C-like proteases. Virus Research, 178(2), 437-444. https://doi.org/10.1016/j.virusres.2013.09.008