Linear, peptidase-resistant beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives with nanomolar affinities to a human somatostatin receptor - Preliminary communication

• Published in: Helvetica chimica acta Vol. 84; no. 11; pp. 3503 - 3510
• Main Authors: Seebach, D, Rueping, M, Arvidsson, PI, Kimmerlin, T, Micuch, P, Noti, C, Langenegger, D, Hoyer, D
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.01.2001
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; SIDE-CHAINS; CD; HELICAL SECONDARY STRUCTURE; METHANOL; DE-NOVO DESIGN; HEXAPEPTIDE; ANALOGS; CYCLO-BETA-TETRAPEPTIDE; GROWTH; NMR STRUCTURE
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/1522-2675(20011114)84:11<3503::AID-HLCA3503>3.0.CO;2-A

N-Acyl-beta (2)/beta (3)-dipeptide-amide somatostatin analogs, 5-8, with beta (2)-HTrp-beta (3)-HLys ('natural' sequence) and beta (2)-HLys-beta (3)-HTrp (retro-sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N-acyl and terminal C-amino group, the linear P-dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to > 10000 nanomolar (Fig. 3). Also, N-Ac-tetrapeptide amides 9 and 10, which contain one alpha- and three beta -amino acid residues have been prepared (solid-phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro-sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel 'mixed', linear alpha/beta -peptides have affinities for the hsst 4 receptor ranging from 23 to > 10000 nanomolar (Fig. 4), and, like 'pure' beta -peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin (Fig. 1) can be mimicked by simple linear di- and tetrapeptides. The tendency of beta -dipeptides for forming hydrogen-bonded rings is confirmed by calculations at the B3LYP/6-31G(d,p) level (Fig. 2). The reported results open new avenues for the design of low-molecular-weight peptidic drugs.