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Template-constrained cyclic peptide analogues of somatostatin: subtype-selective binding to somatostatin receptors and antiangiogenic activity.

Abstract
Beta-turns are a common secondary structure motif found in proteins that play a role in protein folding and stability and participate in molecular recognition interactions. Somatostatin, a peptide hormone possessing a variety of therapeutically-interesting biological activities, contains a beta-turn in its bioactive conformation. The beta-turn and biological activities of somatostatin have been succesfully mimicked in cyclic hexapeptide analogues. Two novel, structured, non-peptidic molecules were developed that are capable of holding the bioactive tetrapeptide sequence of somatostatin analogues in a beta-turn conformation, as measured by somatostatin receptor (SSTR) binding. Template-constrained cyclic peptides in which the ends of the -Tyr-D-Trp-Lys-Val-tetrapeptide were linked by scaffolds based on either an N,N'-dimethyl-N,N'-diphenylurea or a substituted biphenyl system (DJS631 and DJS811, respectively), bound selectively to mouse SSTR2B and rat and human SSTR5 with affinities as high as 1 nM. DJS811, at a dose of 3 mg/kg/day, was shown in a mouse Matrigel model to inhibit angiogenesis to a level of 79%. The development of structured turn scaffolds allows beta-turn sequences to be contained in the context of a compact structure, with less peptidic nature and potentially greater bioavailability than cyclic hexapeptides. These systems can be used to study the determinants of beta-turn formation, as well as to probe the importance of turn sequences occurring in molecular recognition interactions. The antiangiogenic activity of DJS811 suggests that it may have antitumor activity as well. In addition, because SSTR2 is overexpressed on many types of tumors, DJS631 and DJS811 may be useful in the development of agents for tumor imaging or the radiotherapy of cancer.
AuthorsD J Suich, S A Mousa, G Singh, G Liapakis, T Reisine, W F DeGrado
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 8 Issue 9 Pg. 2229-41 (Sep 2000) ISSN: 0968-0896 [Print] England
PMID11026536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • DJS 631
  • DJS 811
  • Peptides, Cyclic
  • Phenylurea Compounds
  • Receptors, Somatostatin
  • Somatostatin
Topics
  • Angiogenesis Inhibitors (metabolism)
  • Animals
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Models, Animal
  • Molecular Mimicry
  • Neovascularization, Physiologic (drug effects)
  • Peptides, Cyclic (chemical synthesis, metabolism, pharmacology)
  • Phenylurea Compounds (chemical synthesis, metabolism, pharmacology)
  • Protein Binding
  • Protein Structure, Secondary
  • Rats
  • Receptors, Somatostatin (metabolism)
  • Somatostatin (analogs & derivatives)
  • Structure-Activity Relationship
  • Thermodynamics

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