Novel Long-Acting Somatostatin Analog with Endocrine Selectivity: Potent Suppression of Growth Hormone But Not of Insulin

Abstract

Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastrointestinal secretion. Its long-acting analogs are in clinical use for treatment of various endocrine syndromes and gastrointestinal anomalies. These analogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable physiological selectivity. Our goal was to design effective and physiologically selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide libraries constructed on the basis of molecular modeling of known SRIF agonists and of high throughput receptor binding assays with each of the five cloned human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PTR-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same nanomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficiently as the drug octreotide, indicating its agonistic effect in this human cell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest that PTR-3173 is the first highly selective somatostatinergic analog for the in vivo inhibition of GH secretion, with minimal or no effect on glucagon and insulin release, respectively.

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

“…We herein report the in vitro effect of DG3173 in a large number of somatotroph adenomas, extending a previous report (24). In addition, we investigated possible correlations of GH suppression with presurgical SSA therapy, hormonal expression of the tumour, tumour morphology and sst expression.…”

“…Furthermore, the potency of DG 3173 to inhibit GH secretion in vitro is 10.000-fold higher than its inhibition of insulin secretion (24). This low insulinsuppressing activity was also demonstrated in vivo (A Steuernagel, C Meyer, R Wehr and C Dohrmann, unpublished results).…”

“…DG3173 is a new SSA that binds to sst2 and sst5, and also binds with nanomolar affinity to sst4. Importantly, it has only low insulin-suppressing activity (24). Thus, DG3173 may prove to be at least as efficient, as well as even more specific as already existing SSA.…”

“…DG3173 is a heptapeptide SSA with a novel amino acid sequence and a unique cyclic backbone (24). In addition to its affinities to sst2 and sst5, DG3173, previously named PTR-3173, is the only SSA binding with nanomolar affinity to sst4 (24).…”

“…In addition to its affinities to sst2 and sst5, DG3173, previously named PTR-3173, is the only SSA binding with nanomolar affinity to sst4 (24). mRNA for sst4 is rarely detected in human pituitary adenomas (25,26) and immunohistochemical staining for sst4 protein has given contradictory results.…”