Development of conformationally restricted analogues of bradykinin and somatostatin using constrained amino acids and different types of cyclization.
The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the N(alpha)-, C(alpha)- and C(beta)-atom as well as at the aromatic ring atom were successfully applied to obtain potent and stable analogues of bradykinin and somatostatin, which due to their restricted conformation were suitable objects for conformational studies. Besides the generation of constrained cyclic analogues with improved biological and pharmacological properties, cyclic peptides were used as convenient models for the study of turn formations. Cyclization of the linear peptide bradykinin was performed by linking the N-terminus and the C-terminus, and in both bradykinin and somatostatin by cyclization using the amino acid side chains and by backbone cyclization. The later requires the introduction of N(alpha)-functionalised amino acids for ring closure which can be performed either through incorporation of N(alpha)-functionalised amino acids or dipeptide building units. Conformational analysis of a cyclic bradykinin analogue by means of NMR-studies together with molecular dynamics simulation led to a quasicyclic 3D structure with two turns and together with other 3D structures provided a pharmacophore model of bradykinin antagonists.
Reissmann
Siegmund
S
Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Philosophenweg 12, D-07743 Jena, Germany. reissmann@merlin.biologie.uni-jena.de
Imhof
Diana
D
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000596:Amino Acids; D013004:Somatostatin; D001920:Bradykinin