Peptide Folding Induces High and Selective Affinity of a Linear and Small β-Peptide to the Human Somatostatin Receptor 4

Abstract

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 hsst_1-5, which is known to rest upon a turn containing the amino acid residues Thr, Lys, Trp, and Phe. The N-acetyl-peptide amide Ac-β³-HThr-β²-HLys-β³-HTrp-β³-HPhe-NH₂ (1) indeed shows all characteristics of the targeted turn-mimic: 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.