A Backbone-Cyclic, Receptor 5-Selective Somatostatin Analogue:  Synthesis, Bioactivity, and Nuclear Magnetic Resonance Conformational Analysis

Abstract

Cyclo(PheN2-Tyr-D-Trp-Lys-Val-PheC3)-Thr-NH2 (PTR 3046), a backbone-cyclic somatostatin analogue, was synthesized by solid-phase methodology. The binding characteristics of PTR 3046 to the different somatostatin receptors, expressed in CHO cells, indicate high selectivity to the SSTR5 receptor. PTR 3046 is highly stable against enzymatic degradation as determined in vitro by incubation with rat renal homogenate and human serum. The biological activity of PTR 3046 in vivo was determined in rats. PTR 3046 inhibits bombesin- and caerulein-induced amylase and lipase release from the pancreas without inhibiting growth hormone or glucagon release. The major conformation of PTR 3046 in CD3OH, as determined by NMR, is defined by a type II' beta-turn at D-Trp-Lys and a cis amide bond at Val-PheC3.

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

“…Backbone cyclization of peptides is the method of cyclization developed and used in our lab. It results in peptides with improved selectivity, enhanced metabolic stability, and high bioavailability (5)(6)(7)(8)(9). To select the most active backbone cyclic (BC) 1 peptide based on a given sequence, we have developed the "cycloscan" technology (10), which involves the structure-based design, synthesis, and screening of BC peptide libraries.…”

“…These parameters include ring size, position, and chemistry. The feasibility of these methodologies has been demonstrated with several naturally occurring peptides, including substance P (6,7,10,11), somatostatin (9), and pheromone biosynthesis activating neuropeptide (5), resulting in the development of receptor-selective and metabolically stable BC peptides.…”

Backbone Cyclic Peptide Antagonists, Derived from the Insect Pheromone Biosynthesis Activating Neuropeptide, Inhibit Sex Pheromone Biosynthesis in Moths

“…Preparation of backbone cyclic (BBC) 1 peptides involves the use of a large variety of orthogonally protected N ␣ and C ␣ (-amino-, -carboxy-, and -thio-alkyl) amino acids building units (4 -6). Synthetic procedures have been developed to incorporate these building units into peptides using the solid phase methodology (7,8).The advantages of backbone cyclization over the naturally occurring modes of cyclization are because of the immense variability of spatial orientation of the constitute residues which result from the multiple anchoring points within a chain or between chains. This allows us to screen the conformational space of a given peptide in an extremely efficient manner.…”

“…Preparation of backbone cyclic (BBC) 1 peptides involves the use of a large variety of orthogonally protected N ␣ and C ␣ (-amino-, -carboxy-, and -thio-alkyl) amino acids building units (4 -6). Synthetic procedures have been developed to incorporate these building units into peptides using the solid phase methodology (7,8).…”

“…Furthermore, most of the modes of backbone cyclization do not involve chemical modifications of side chains which are essential for biological activity. Backbone cyclization has been shown previously to convert peptides into selective and metabolically stable peptidomimetics with enhanced biological activity as compared with the linear parent peptide (7)(8)(9)(10).…”