Linear, peptidase-resistant β 23-Di- and α/β 3-tetrapeptide derivatives with nanomolar affinities to a human somatostatin receptor

Dieter Seebach*, Magnus Rueping, Per I. Arvidsson, Thierry Kimmerlin, Peter Micuch, Christian Noti, Daniel Langenegger, Daniel Hoyer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

N-Acyl-β 33-dipeptide-amide somatostatin analogs, 5-8, with β 2-HTrp-β 3-HLys ('natural' sequence) and β 2-HLys-β 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 β-dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to > 10000 nanomolar (Fig. 3). Also, N-Actetrapeptide amides 9 and 10, which contain one α- and three β-amino acid residues (N-β-α-β-β-C), 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 α/β-peptides have affinities for the hsst 4 receptor ranging from 23 to > 10000 nanomolar (Fig. 4), and, like 'pure' β-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 β-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.

Original languageEnglish (US)
Pages (from-to)3503-3510
Number of pages8
JournalHelvetica Chimica Acta
Volume84
Issue number11
DOIs
StatePublished - Dec 31 2001

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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