Peptides and peptidomimetics as immunomodulators

Abstract

Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically.

Keywords: T-cell epitope; cyclotide; immunomodulation; peptide-based vaccine; peptidomimetics; β-amino acid.

Figure 1. Crystal structures of protein complexes that are involved in adhesion or costimulation during immune response

An array of these molecules on the T cell and antigen-presenting cell facilitates the contact between the cells apart from TCR-MHC molecules. (A) CD2-CD58 (Protein Data Bank ID: 1AQ9), (B) B7-CTL-4 (Protein Data Bank ID: 1I8L), (C) LFA-1-ICAM-1 (Protein Data Bank ID: 1MQ8) and (D) TCR-MHC (Protein Data Bank ID: 1G6R). CTL: Cytotoxic T lymphocyte; LFA: Leukocyte function-associated antigen; TCR: T-cell receptor.

Figure 2. Design strategy for peptidomimetics

(A) Epitope of a protein that has relevant biological function identified from functional studies. Peptidomimetic design based on (B) backbone modifications, (C) side-chain modifications using amino acid analogs and (D) secondary structures such as α-helix or β-turn mimetics [,–29]. (E) Examples of peptidomimetics that are therapeutically useful for cardiovascular disease [26].

Figure 3. Hot spot in CD2-CD58 structure used for the design of CD2-based peptides for immunomodulation

Tyr86 and Phe46 sandwich the Lys34 forming a hydrophobic interaction. Mutation of Tyr86 by Ala results in complete loss of binding of CD2 protein to CD58 suggesting hot-spot residues in the interaction of CD2 and CD58 [44].

Figure 4. Design of a peptidomimetic for immunomodulation

(A) Based on the hot-spot region of F and C strands of CD2 protein that binds to CD58, epitopes of secondary structure of CD2 protein were chosen. (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]. DBF: Dibenzofuran.

Figure 5. Design concept of bifunctional peptides

The peptide sequence that binds to molecule (A) can be antigenic, and the peptide sequence that binds to (B) is specific for a surface receptor protein or cell adhesion molecule that is involved in immunomodulation. The two peptide sequences can be linked by glycine linker or by amino caproic or hexanoic acid or polyethylene glycol linkers. Using this strategy, both the peptide sequences bind simultaneously to two receptors. These peptide sequences can be modified to peptidomimetics for enzymatic stability [60,65,70].

Figure 6. Design of an immunogenic peptide

Linear or conformationally constrained peptides can be designed to generate an immune response for a particular antigenic sequence [94,98].

Figure 7. Structure of a cyclotide that can be used for grafting an epitope

L represents the loops that can be used for grafting peptide sequences. N and C refer to peptide N- and C-terminals, respectively. Disulfide bonds that form the knot are shown by sticks [128].