Contribution of Conformationally Constrained Calcitonin (Ct) Analogs to the Understanding of the Structural and Conformational Requirements of Calcitonin Bioactivity and to the Design of Potent Agonists

Abstract

Restricting the conformational flexibility of medium-sized linear polypeptides is a valuable approach to identify and characterize the structural and conformational features that define their biological activities and to design analogs with enhanced agonistic or antagonistic properties and with potential therapeutic applications. The calcium-regulating and bone resorption-inhibiting hormone calcitonin (Ct) is a conformationally flexible polypeptide of 32 amino acid residues that has long been applied therapeutically for the treatment of osteoporosis and other bone disorder diseases. This review describes studies on the structural and conformational features of the Ct sequence that are relevant for Ct bioactivity and focuses on research work performed on rationally designed conformationally constrained Ct analogs as tools for the understanding of the molecular basis of Ct bioactivity and as potential candidates or lead structures for novel Ct-based bone disorder therapeutics.

Three-Dimensional Structure and Orientation of Rat Islet Amyloid Polypeptide Protein in a Membrane Environment by Solution NMR Spectroscopy

“…Relatively little is known about structure–activity relationships for IAPP’s normal biological action in comparison to its pathological aggregation. Experiments on truncated versions of calcitonin and CGRP (the closest homologue of IAPP) have shown that the formation of the amphipathic helix is sufficient for receptor binding but activation of the receptor requires the N-terminal ring 66. Removal of the N-terminal ring or reduction of the disulfide bridge results in CGRP binding to its receptor in an inactive conformation.…”

“…All of the peptides in this family possess an amidated C-terminus, an amphipathic helix near the N-terminus, a largely disordered C-terminus, and an N-terminal ring connected by a disulfide bond. − Two binding sites have been proposed for the binding of peptides of this family to the membrane-bound receptor: one near the membrane surface that would be consistent with the orientation found in this study for rIAPP and another requiring a more deeply inserted membrane orientation as found for hIAPP 1−19 and hypothesized for hIAPP. ,, Relatively little is known about structure−activity relationships for IAPP’s normal biological action in comparison to its pathological aggregation. Experiments on truncated versions of calcitonin and CGRP (the closest homologue of IAPP) have shown that the formation of the amphipathic helix is sufficient for receptor binding but activation of the receptor requires the N-terminal ring . Removal of the N-terminal ring or reduction of the disulfide bridge results in CGRP binding to its receptor in an inactive conformation.…”

“…Experiments on truncated versions of calcitonin and CGRP (the closest homologue of IAPP) have shown that the formation of the amphipathic helix is sufficient for receptor binding but activation of the receptor requires the N-terminal ring. 66 Removal of the N-terminal ring or reduction of the disulfide bridge results in CGRP binding to its receptor in an inactive conformation. A similar N-truncated rIAPP construct (rIAPP 8-37 ) has been shown to act as an antagonist for rIAPP's effects on insulin secretion and carbohydrate and lipid metabolism.…”