We had previously identified several E protein regions where peptides mimicking the E protein sequence might function as inhibitors. Several of these mimic peptides did not show substantial DENV inhibitory activity [9] . These included a peptide derived from the domain II fusion sequence (DN80, corresponding to amino acids 96-114 in the DENV-2 E protein) and two overlapping peptides derived from the domain II hinge region (DN57 and DN81, corresponding to amino acids 205-223 and 205-232, respectively). Predictions from crystal structures [11, 14, 15] , as well as the previously confirmed inhibitory activity of an analogous WNV domain II hinge region peptide [9] lent support to the idea that the domain II hinge region was an attractive target for inhibition. Energy minimized peptides with sequences computationally optimized for structural stability and binding to the target regions, as evaluated by our residue-specific all-atom probability discriminatory function (RAPDF), were selected for further characterization and evaluation. These sequences generally had the best RAPDF scores (or ''pseudoenergies'') for structural stability and binding, much better (lower) than the original wild type sequences (see Table 1 for original and optimized sequences.). These sequences, DN57opt, DN80opt and DN81opt, were selected for synthesis and evaluated for antiviral activity.