Peptide folding induces high and selective affinity of a linear and small beta-peptide to the human somatostatin receptor 4

beta -Peptides with side chains in the 2- and S-positions on neighboring re sidues (of (S) configuration) are known to fold and form a turn (similar to an alpha -peptidic beta -turn). Thus, we have synthesized an appropriately substituted beta -tetrapeptide derivative to mimic the hormone somatostati n in its binding to the human receptors hsst(1-5), which is known to rest u pon a turn containing the amino acid residues Thr, Lys, Trp, and Phe. The N -acetyl-peptide amide Ac-beta (3)-HThr-beta (2)-HLys-beta (3)-HTrp-beta (3) -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 ana lysis, Figure 2) and there is high and specific nanomolar affinity for hsst (4) receptor (Table 1). In contrast, the isomer 2 bearing the Lys side chai n in 3-, rather than in the 2-position, has a 1000-fold smaller affinity to hsst(4). The syntheses of the required Fmoc-protected beta -amino acids (8 -11, 17) are described (Schemes 1-3). Coupling of the beta -amino acids was achieved by the manual solid-phase technique, on Rink resin.