Small molecule inhibitors that selectively block dengue virus methyltransferase

Siew Pheng Lim, Louis Sebastian Sonntag, Christian Noble, Shahul H. Nilar, Ru Hui Ng, Gang Zou, Paul Monaghan, Ka Yan Chung, Hongping Dong, Boping Liu, Christophe Bodenreider, Gladys Lee, Mei Ding, Wai Ling Chan, Gang Wang, Yap Li Jian, Alexander Theodore Chao, Julien Lescar, Zheng Yin, T. R. VedanandaThomas H. Keller, Pei Yong Shi

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.

Original languageEnglish (US)
Pages (from-to)6233-6240
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number8
DOIs
StatePublished - Feb 25 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lim, S. P., Sonntag, L. S., Noble, C., Nilar, S. H., Ng, R. H., Zou, G., Monaghan, P., Chung, K. Y., Dong, H., Liu, B., Bodenreider, C., Lee, G., Ding, M., Chan, W. L., Wang, G., Jian, Y. L., Chao, A. T., Lescar, J., Yin, Z., ... Shi, P. Y. (2011). Small molecule inhibitors that selectively block dengue virus methyltransferase. Journal of Biological Chemistry, 286(8), 6233-6240. https://doi.org/10.1074/jbc.M110.179184