Synthesis of Oligo(3-hydroxybutanoate)(OHB)-Containing Peptides with High Binding Affinity to a Class-I-MHC Protein

Article abstract of DOI:10.1002/hlca.19980810529

In the center of the immune system, there are major histocompatibility (MHC) protein/nonapeptide complexes which are recognized by T cells. The nonapeptides consist of three regions, an N-terminal one containing three amino-acid residues with a mandatory arginine in position 2, a C-terminal one with a lysine or arginine in position 9, and a central, variable one of five residues (cf. Fig. 1). We have now synthesized the first conjugates (1-4) of oligopeptides with oligo[(R)-3-hydroxybutanoates] (OHB) as analogs of MHC-binding peptides. Of the approaches chosen (Scheme 1), a fragment coupling of a hydroxy-butanoyl-amido ester (17 and 19) with an [(aminoalkanoyl)oxy]butanoyl chloride (27; Scheme 3), followed by two peptide-coupling steps (Scheme 4), turned out to be most efficient. The conjugates H-Gln-Arg-Leu-(HB)_3,4-Lys-OH (1 and 2) and H-Ala-Arg-Leu-(HB)_3,4-Lys-OH (3 and 4) were thus obtained in pure form. The conjugates 1 and 2 with N-terminal glutamine have a tendency to undergo cyclization with formation of a pyroglutamate residue (cf. Fig. 2). CD Measurements at different temperatures and so-called epitope-stabilization assays show that the complexes of the conjugates 2 and 4, containing four HB units, with the HLA-B27 class-I-MHC protein are more stable than those of a model nonapeptide (C₅₀ values of 2.25 and 1.60 μM vs. 10 μM), while the conjugates 1 and 3 with three HB units incorporated form less stable complexes (C₅₀ values of 30 and 21 μM). The tetra(hydroxybutanoate)-peptide conjugates 2 and 4 are the first nonapeptide analogs for which the modification of the central part leads to increased affinities for a class-I-MHC protein, as compared to a model nonapeptide.