A small molecule fusion inhibitor of dengue virus
2009; Elsevier BV; Volume: 84; Issue: 3 Linguagem: Inglês
10.1016/j.antiviral.2009.09.011
ISSN1872-9096
AutoresMee Kian Poh, Andy M. Yip, Summer L. Zhang, John P. Priestle, Ngai Ling, Jolanda M. Smit, Jan Wilschut, Pei‐Yong Shi, Markus R. Wenk, Wouter Schul,
Tópico(s)Viral Infections and Outbreaks Research
ResumoThe 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.
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