A small molecule fusion inhibitor of dengue virus

Mee Kian Poh, Andy Yip, Summer Zhang, John P. Priestle, Ngai Ling Ma, Jolanda M. Smit, Jan Wilschut, Pei Yong Shi, Markus R. Wenk, Wouter Schul

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Abstract

The dengue virus envelope protein plays an essential role in viral entry by mediating fusion between the viral and host membranes. The crystal structure of the envelope protein shows a pocket (located at a "hinge" between Domains I and II) that can be occupied by ligand n-octyl-β-d-glucoside (βOG). Compounds blocking the βOG pocket are thought to interfere with conformational changes in the envelope protein that are essential for fusion. Two fusion assays were developed to examine the anti-fusion activities of compounds. The first assay measures the cellular internalization of propidium iodide upon membrane fusion. The second assay measures the protease activity of trypsin upon fusion between dengue virions and trypsin-containing liposomes. We performed an in silico virtual screening for small molecules that can potentially bind to the βOG pocket and tested these candidate molecules in the two fusion assays. We identified one compound that inhibits dengue fusion in both assays with an IC50 of 6.8 μM and reduces viral titers with an EC50 of 9.8 μM. Time-of-addition experiments showed that the compound was only active when present during viral infection but not when added 1 h later, in agreement with a mechanism of action through fusion inhibition.

Original languageEnglish (US)
Pages (from-to)260-266
Number of pages7
JournalAntiviral research
Volume84
Issue number3
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

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Keywords

  • Antiviral
  • Dengue virus
  • Fusion inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Poh, M. K., Yip, A., Zhang, S., Priestle, J. P., Ma, N. L., Smit, J. M., Wilschut, J., Shi, P. Y., Wenk, M. R., & Schul, W. (2009). A small molecule fusion inhibitor of dengue virus. Antiviral research, 84(3), 260-266. https://doi.org/10.1016/j.antiviral.2009.09.011