Partially Modified Retro-Inverso Pseudopeptides as Non-natural Ligands for the Human Class I Histocompatibility Molecule HLA-A2

• Published in: Journal of medicinal chemistry 1996-05, Vol.39 (10), p.2030-2039
• Main Authors: Guichard, Gilles, Connan, Francine, Graff, Roland, Ostankovitch, Marina, Muller, Sylviane, Guillet, Jean-Gérard, Choppin, Jeannine, Briand, Jean-Paul
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; HLA-A2 Antigen - metabolism; Humans; Immunomodulators; Ligands; Medical sciences; Molecular Sequence Data; Orthomyxoviridae - metabolism; Peptides - chemistry; Peptides - metabolism; Pharmacology. Drug treatments; Protein Binding; Spectrometry, Mass, Fast Atom Bombardment; Tumor Cells, Cultured; Viral Matrix Proteins - chemistry; Viral Matrix Proteins - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9509511

Syntheses of a series of partially modified retro-inverso analogues of the antigenic peptide M58-66 derived from the influenza virus matrix protein are reported. The retro-inverso modification Ψ(NH−CO) was obtained by replacement of two successive amino acid residues with a 2-substituted malonate derivative and gem-diaminoalkyl residue. The resulting compounds 1−8 were tested for their binding to the human histocompatibility class I molecule HLA-A2 in an assembly assay using lysates of peptide transporter-deficient cells T2. Specific peptide-dependent HLA-A2 assembly was revealed by an enzyme-linked immunosorbent assay. Significant HLA-A2 assembly was detected in the presence of analogues [gGly58-(S)mLeu59]M58-66 (1a), [gGly61-(R,S)mPhe62]M58-66 (4), [gVal63-(R,S)mPhe64]M58-66 (6), and [gPhe64-(R,S)mAla65]M58-66 (7). The introduction of the retro-inverso modification between P2−P3, P3−P4, P5−P6, and P8−P9 (compounds 2, 3, 5, and 8, respectively) however led to a dramatic reduction in peptide binding to HLA-A2. Interestingly, compound 1a which contains modification between P1−P2 was found to be the most potent analogue, being able to retain the original HLA-A2 binding profile of the parent peptide M58-66. Taken together, these results and recent binding data obtained in the context of murine MHC class I molecule H-2Kd suggest that the incorporation of peptide bond surrogates in MHC class I-restricted epitopes is a useful approach to design molecules having both increased stability and high MHC-binding capacity. Depending on their agonist or antagonist effects at the T-cell receptor, such non-natural MHC ligands are likely to find many applications in the development of peptide-based vaccines or as potential therapeutic agents in the treatment of allergies and autoimmune diseases.