科研之友
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摘要
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-beta-D-glucoside (beta OG). Compounds blocking the beta OG 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 beta OG pocket and tested these candidate molecules in the two fusion assays. We identified one compound that inhibits dengue fusion in both assays with an IC(50) Of 6.8 mu M and reduces viral titers with an EC(50) of 9.8 mu M. 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.
- 出版日期2009-12
