Conformationally constrained peptides from CD2 to modulate protein-protein interactions between CD2 and CD58.

Cell adhesion molecule CD2 and its ligand CD58 provide good examples of protein-protein interactions in cells that participate in the immune response. To modulate the cell adhesion interaction, peptides were designed from the discontinuous epitopes of the β-strand region of CD2 protein. The two strands were linked by a peptide bond. β-Strands in the peptides were nucleated by inserting a β-sheet-inducing (D)-Pro-Pro sequence or a dibenzofuran (DBF) turn mimetic with key amino acid sequences from CD2 protein that binds to CD58. The solution structures of the peptides (5-10) were studied by NMR and molecular dynamics simulations. The ability of these peptides to inhibit cell adhesion interaction was studied by E-rosetting and lymphocyte epithelial assays. Peptides 6 and 7 inhibit the cell adhesion activity with an IC(50) of 7 and 11 nM, respectively, in lymphocyte epithelial adhesion assay. NMR and molecular modeling results indicated that peptides 6 and 7 exhibited β-hairpin structure in solution.