Human Somatostatin Receptor Specificity of Backbone-Cyclic Analogues Containing Novel Sulfur Building Units

Abstract

Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.

Aqueous-Soluble, Non-Reversible Lipid Conjugate of Salmon Calcitonin: Synthesis, Characterization and In Vivo Activity

“…For example, the replacement of the disulfide moiety in desmopressin with a sulfideYmethylene group resulted in a longer duration of activity (14). An analogue of octreotide, PTR 3173, which did not have an intra-disulfide bond, was shown to be as potent as octreotide in inhibiting forskolin-stimulated cAMP accumulation in several cell lines (15,16). Linear salmon calcitonin (sCT) analogues without an intra-disulfide bond also possessed intact hypocalcemic activity in the rat model (17).…”

Improvement of drug-like properties of peptides: the somatostatin paradigm

“…0.05 --0.4 PTR-3173 [85] > 1000 3 ± 0.75 > 100 7 ± 1.1 1 ± 0.05 > 1000 PTR-3046 [83] > 1000 > 1000 optimal orientation of the side chains is the so-called 'spatial screening' technology ( Figure 3). This approach allows the presentation of the side chains in different spatial orientations while the backbone conformation is completely retained [71].…”

“…The development of sulfur-containing building units for BC enabled the synthesis of BC disulfide bridged analogs based on the structure of PTR-3173 [85]. These analogs were also evaluated for the stability and affinity at the sst receptors, and compared to PTR-3173.…”

“…Changing the ring size from 28 to 26 atoms caused diminished affinity towards sst3, while retaining the activation of sst2 and 5. Moreover, an analog with the same selectivity pattern was achieved by replacing the lactam bridge by a backbone disulfide bridge [85].…”

Amelioration of experimental autoimmune encephalitis by novel peptides: Involvement of T regulatory cells

“…Since MS is a prolonged disease, our challenge was to develop a compound that can be taken orally. Several studies have shown that cyclization of peptides conferred metabolic stability [28] and better penetration through the gastrointestinal tract [29]. Therefore, we tested the effect of oral administration of a cyclic form of the peptide while IIIM1 was taken as a negative control, starting the treatment at onset of symptoms (usually 7 d after MOG immunization).…”