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Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines.

Mazumder R, Hu ZZ, Vinayaka CR, Sagripanti JL, Frost SD, Kosakovsky Pond SL, Wu CH

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.

We have identified 72 completely conserved amino acid residues in the E protein of major groups of the Flavivirus genus by computational analyses. In the dengue species we have identified 12 highly conserved sequence regions, 186 negatively selected sites, and many dengue serotype-specific negatively selected sites. The flavivirus-conserved sites included residues involved in forming six disulfide bonds crucial for the structural integrity of the protein, the fusion motif involved in viral infectivity, and the interface residues of the oligomers. The structural analysis of the E protein showed 19 surface-exposed non-conserved residues, 128 dimer or trimer interface residues, and regions, which undergo major conformational change during trimerization. Eleven consensus T(h)-cell epitopes common to all four dengue serotypes were predicted. Most of these corresponded to dengue-conserved regions or negatively selected sites. Of special interest are six singular sites (N(37), Q(211), D(215), P(217), H(244), K(246)) in dengue E protein that are conserved, are part of the predicted consensus T(h)-cell epitopes and are exposed in the dimer or trimer. We propose these sites and corresponding epitopic regions as potential candidates for prioritization by experimental biologists for development of diagnostics and vaccines that may be difficult to circumvent by natural or man-made alteration of dengue virus.

Published 19 July 2007 in Virus Genes, 35(2): 175-86.
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