Constrained Analogs of Osteogenic Peptides

Gordon   E.   Willick; Paul      Morley; James   F.   Whitfield

Abstract

Osteogenic peptides are, or have potential to be, therapies for the treatment of osteoporosis, fracture repair, and repair of loosened bone implants. Human parathyroid hormone has been approved for the treatment of post-menopausal osteoporosis. Constrained analogs of PTH and the parathyroid-hormone related peptide (PTHrP) have aided the understanding of how PTH and PTHrP bind to their common receptor and some of these analogs have improved properties that make them possible candidates for clinical trial. Cyclization by lactam formation has shown that a core region of human PTH (hPTH) from residues 16-26 binds as an α-helix to the receptor and that the biological effects are remarkably sensitive to ring size. Appropriate cyclization in this region of the molecule not only has yielded analogs with improved receptor activation but also ones less susceptible to protease degradation and thus more active in vivo. Cyclization has been less successful in the Nterminus region, residues 1-12, of hPTH(1-34) with only a cyclization between residues 6 and 10 showing some promise. The growing understanding of how this region binds to the receptor will lead to other productive constraints. This review also covers the potential of a different class of molecule, the osteogenic growth peptide (OPG), as an anabolic bone agent. These molecules have much weaker anabolic effects than PTH and cyclization does not result in improved activity. However, the information gained from these studies may yield analogs with better pharmacological profiles.

Keywords: peptide, lactam, constrained, parathyroid, osteoporosis

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