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

• DOI: 10.1021/jm010816q
• Publication Date: 2002-07-26T04:39:39Z
• Authors: Karl Gademann; Thierry Kimmerlin; Daniel Hoyer; Dieter Seebach
• Keywords: folding; Protein Folding; Magnetic Resonance Spectroscopy; receptor binding; Circular Dichroism; Molecular Mimicry; Membrane Proteins; somatostatin; Octreotide; 01 natural sciences; Protein Structure, Secondary; Recombinant Proteins; Cell Line; 0104 chemical sciences; Radioligand Assay; peptide mimic; Humans; Receptors, Somatostatin; Somatostatin; Oligopeptides

beta-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 alpha-peptidic beta-turn). Thus, we have synthesized an appropriately substituted beta-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-beta(3)-HThr-beta(2)-HLys-beta(3)-HTrp-beta(3)-HPhe-NH(2) (1) indeed shows all characteristics of the targeted turn-mimic: Lys CH(2) 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 hsst(4) 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 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.