Linear, Peptidase-Resistantβ2/β3-Di- andα/β3-Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor, Preliminary Communication

Abstract

Nervous System Research, S-386-745, Novartis Pharma AG, CH-4002 Basel N-Acyl-b 2 /b 3 -dipeptide-amide somatostatin analogs, 5 ± 8, with b 2 -HTrp-b 3 -HLys (×natural× sequence) and b 2 -HLys-b 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 b-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 a-and three b-amino acid residues (N-b-a-b-b-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 a/b-peptides have affinities for the hsst 4 receptor ranging from 23 to > 10000 nanomolar (Fig. 4), and, like −pure× b-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 b-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-molecularweight peptidic drugs. b-Peptides have recently emerged as a promising class of peptidomimetics for medicinal chemistry. The ability of b-peptides (for reviews, see [1]) to adopt secondary structures such as helices [1], sheets [2a] [3], and, especially, turns [3] suggests that these compounds might be structural and functional mimics of natural peptides. The potential of such mimics is evident from the facts that a) these secondary structures can be readily designed [1 ± 5], and that b) the b-peptides are completely stable against proteolytic degradation in vitro and in vivo [2a] [6].So far, b-peptides, designed to form amphiphilic helices, have been shown to inhibit an intestinal membrane-bound cholesterol-and lipid-transporting protein [5]. Also, similar peptides have been shown to possess antimicrobial, and sometimes, hemolytic activities [7].

-Hairpins Generated from Hybrid Peptide Sequences Containing both - and -Amino Acids

“…This approach is of relevance in the generation of biologically active peptide analogs exhibiting resistance to proteolysis, with susceptible cleavage sites modified by insertion of bresidues [21] [22].…”

Design and selection of nitrogen-rich bridged di-1,3,5-triazine derivatives with high energy and reduced sensitivity

“…The isodesmic reaction method was employed to calculate their HOFs, using the total energies obtained from DFT-B3LYP/6-31G(d,p) calculations. This approach has been demonstrated to reliably predict the HOFs of many organic systems via isodesmic reactions [3,4,[34][35][36][37][38][39]. We designed isodesmic reactions in which the numbers of all kinds of bonds were kept constant, in order to decrease the HOF calculation errors.…”

Biological Applications of Foldamers

“…The strategy is most likely to be productive if the mere presence of the bioactive functionalities is sufficient to exert bioactivity (which is rare), or if the foldamer scaffold inherently presents the bioactive functionalities with a similar spatial arrangement compared to the natural biopolymer and the backbone is not directly involved in binding. For example, somatostatin receptor binding b-peptides adopt a turn structure similar to the natural a-peptide somatostatin [149][150][151]. However, biologically active molecules often present functionalities in orientations significantly different from foldamer scaffolds, and therefore more sophisticated design strategies are necessary.…”

“…The cyclic b-peptides bound different types of human somatostatin receptors with micromolar affinities (K D ¼ 3.3- 186 mM). Interestingly, unconstrained linear b-peptides, that adopt a turn conformation, bound somatostatin receptors with nanomolar affinities (K D ¼ 83-724 nM) [151,169], suggesting that the constraints imposed by the cyclic b-peptide were less than optimal.…”