353245-99-5Relevant articles and documents
Melanoma peptide MART-1(27-35) analogues with enhanced binding capacity to the human class I histocompatibility molecule HLA-A2 by introduction of a β-amino acid residue: Implications for recognition by tumor-infiltrating lymphocytes
Guichard,Zerbib,Le Gal,Hoebeke,Connan,Choppin,Briand,Guillet
, p. 3803 - 3808 (2000)
The design of heteroclytic antigens with high MHC binding capacity is of particular interest to overcome the weak immunogenicity of peptide epitopes derived from tissue antigens expressed by tumors. In the present study, double-substituted peptide analogues of the tumor-associated antigen MART-1(27-35) incorporating a substitution at a primary anchor residue and a β-amino acid residue at different positions in the sequence were synthesized and evaluated for binding to the human histocompatibility class I molecule HLA-A2 and for recognition by tumor-infiltrating lymphocytes. Interestingly, by combining a Leu for Ala substitution at P2 (which alone is deleterious for antigenic activity) with a β-amino acid substitution at a putative TCR contact residue, recognition by tumor-infiltrating lymphocytes was partially restored. The analogue [Leu28,β-HIle30]MART-1(27-35) displays both a higher affinity to HLA-A2 and a more prolonged complex stability compared to [Leu28]MART-1(27-35). Overall, these results suggest that double-substitution strategies and β-amino acid replacements at putative TCR contact residues might prove useful for the design of epitope mimics with high MHC binding capacity.
Peptide folding induces high and selective affinity of a linear and small β-peptide to the human somatostatin receptor 4
Gademann,Kimmerlin,Hoyer,Seebach
, p. 2460 - 2468 (2007/10/03)
β-Peptides with side chains in the 2- and 3-positions on neighboring residues (of (S) configuration) are known to fold and form a turn (similar to an α-peptidic β-turn). Thus, we have synthesized an appropriately substituted β-tetrapeptide derivative to mimic the hormone somatostatin in its binding to the human receptors hsst1-5, which is known to rest upon a turn containing the amino acid residues Thr, Lys, Trp, and Phe. The N-acetyl-peptide amide Acβ3-HThr-β2-HLys-β3 -HTrp-β3-HPhe-NH2 (1) indeed shows all characteristics of the targeted turnmimic: Lys CH2 groups are in the shielding cone of the Trp indole ring (by NMR analysis, Figure 2) and there is high and specific nanomolar affinity for hsst4 receptor (Table 1). In contrast, the isomer 2 bearing the Lys side chain in 3-, rather than in the 2-position, has a 1000-fold smaller affinity to hsst4. The syntheses of the required Fmoc-protected β-amino acids (8-11, 17) are described (Schemes 1-3). Coupling of the β-amino acids was achieved by the manual solid-phase technique, on Rink resin.
