Exploration of requirements for peptidomimetic immune recognition. Antigenic and immunogenic properties of reduced peptide bond pseudopeptide analogues of a histone hexapeptide.
We present a detailed analysis of the antigenic and immunogenic properties of a series of very stable peptidomimetics of a model hexapeptide corresponding to the C-terminal residues 130-135 of histone H3. Five pseudopeptide analogues of the natural sequence IRGERA were synthesized by systematically replacing, in each analogue, one peptide bond at a time by a reduced peptide bond Psi(CH2-NH). Three important features of the resulting analogues were examined. First, the analogues were tested in a biosensor system for their ability to bind monoclonal antibodies generated against the parent natural peptide, and their kinetic rate constants were measured. The results show that reduced peptide bond analogues can very efficiently mimic the parent peptide. The position of reduced bonds which were deleterious for the binding was found to depend on the antibody tested, and one monoclonal antibody recognized all five analogues. The equilibrium affinity constant toward reduced peptide bond analogues of four antibodies of IgG1 isotype induced against the parent hexapeptide was higher (up to 670 times) with certain analogues than toward the homologous peptide. Second, immunogenic properties of the five analogues were studied, and it was found that polyclonal antibodies induced against analogues in which Psi(CH2-NH) bonds were introduced between residues 130-131, 131-132, and 132-133 (R1-R2, R2-R3, and R3-R4) cross-reacted strongly with the cognate protein H3. Third, we tested the protease resistance of analogues. Altogether, the results provide a strong support for the potent applicability of reduced peptide bond pseudopeptides as components of synthetic vaccines and open a new field for the development of immunomodulatory agents.
Benkirane
N
N
Institut de Biologie Moléculaire et Cellulaire, UPR 9021 CNRS, 15, rue Descartes, 67000 Strasbourg, France.
Guichard
G
G
Briand
J P
JP
Muller
S
S
D000818:Animals; D000917:Antibody Formation; D004797:Enzyme-Linked Immunosorbent Assay; D006657:Histones; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology*; D011817:Rabbits; D014357:Trypsin / Q000378:metabolism
D006657:Histones; D009842:Oligopeptides; D014357:Trypsin