The DN57opt and 1OAN1 peptides were designed for optimized binding to the pre-fusion E structure and we show direct evidence for this interaction, both with the purified, monomeric E protein, and with virion particles. These peptides likely function by displacing portions of the E protein and interfering with normal cell binding or the structural changes during entry. Although separate in the primary protein sequence, the regions targeted in the design the DN57 and 1OAN1 peptides are partially adjacent to each other in the crystal structure, with the C terminus of the 1OAN1 region occupying a pocket surrounded by the DN57 region (See Figure 1) . We stress that we do not know the structures of the bound and inhibited peptide/ E protein complexes, but these structures may shed light on the mechanistic details of cell binding and fusion. Taken together, our results support the hypothesis that both of these peptides interact directly with DENV-2 E proteins and are entry inhibitors.