Only a few examples of viral entry inhibitors with activity against the primarily beta sheet envelope proteins (E) from flaviviruses have been described [8] [9] [10] . However, few of these have taken advantage of the available crystal structures of flavivirus E proteins, including both pre-fusion and post-fusion forms [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] . The authors of some of these structures have predicted that several regions of these proteins might be targets for inhibition [11, 14, 15] . Here we report the use of structural data from the pre-fusion dengue virus-2 (DENV-2) E protein as a model for a computational approach to the design of new peptide inhibitors of DENV-2 entry. This approach makes use of a residue-specific all-atom probability discriminatory function (RAPDF) score to identify in situ amino acid sequences that are likely to have high structural and binding stability [23, 24] . Out of seven computationally designed peptides that were synthesized and tested, two were identified as possessing fifty percent in vitro inhibitory activity (IC 50 ) below 10 mM and another with IC 50 activity below 40 mM. Two of the inhibitors (DN57opt and DN81opt) are binding optimized variants of peptides originally designed from DENV inhibitory peptide sequences located in domain II near the domain I/domain II hinge region [9] . The other (1OAN1) is an entirely novel peptide designed from an extended beta sheet region comprising the first connection between domains I and II. We show that the two peptides with the highest inhibitory activity interfere with virus:cell binding, cause structural changes to the surface of DENV-2 virions, and bind specifically to purified DENV-2 E protein.