Conformationally Constrained Peptides from CD2 To Modulate Protein–Protein Interactions between CD2 and CD58

Abstract

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 beta-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 IC50 value of 7 nM 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.

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

“…10 In an earlier publication, we described the design of peptide 6, which exhibits a β-strand/β-hairpin structure that is stabilized by a β-turn-inducing d -Pro- l -Pro motif. 11 We used the topology of peptide 6 as well as the F and C strands of CD2 from the crystal structure of CD2 10,20 to design grafted analogs of SFTI and RTD (Figure 1). The disulfide-stabilized, antiparallel β-strand conformation of these molecules (PDB ID: 1JBL, 4TTK, 2LYF, 2ATG) 19,21–23 was utilized as a template to introduce several mutations (Figure 1) to generate mimics of the CD2 F/C strand region.…”

Peptides and Peptidomimetics as Immunomodulators

“…Hence, modulation or blocking of adhesion and costimulatory molecules reduces the inflammatory cell accumulation and modifies the process of inflammation. Based on the PPIs of these molecules, peptides and peptidomimetics have been designed as possible therapeutic agents for RA [40–42]. …”

“…In vivo studies provided encouraging results in suppressing RA in the CIA animal model. Furthermore, the molecules designed suppressed the T-cell immune response in a transgenic animal model and were nonimmunogenic [40,41]. …”

“…(B) Epitopes of CD2 protein from the adhesion domain that have β-strand and β-turn structures. (C) Based on F and C strands, a peptide was designed with backbone cyclization and insertion of β-hairpin, β-turn inducer DBF [3,40,46]. …”

Medicinal Chemistry for 2020

“…The antibody drug alefacept, directed against the PPI modulation, is therapeutically used for severe chronic plaque psoriasis. Small peptides/peptidomimetic molecules are targeted to the CD58 adhesion domain to modulate PPI [145,146]. …”