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Issue 39, 2016
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Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis

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Abstract

Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however it provides an attractive framework for the creation of stable analogues using various peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which showed that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts (bone-forming cells). Importantly, Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail and head-to-side chain macrolactamisation as well as ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed upon macrocyclisation.

Graphical abstract: Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis

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Publication details

The article was received on 08 Jul 2016, accepted on 01 Aug 2016 and first published on 01 Aug 2016


Article type: Paper
DOI: 10.1039/C6OB01455K
Citation: Org. Biomol. Chem., 2016,14, 9225-9238
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    Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis

    Z. Amso, R. Kowalczyk, M. Watson, Y. Park, K. E. Callon, D. S. Musson, J. Cornish and M. A. Brimble, Org. Biomol. Chem., 2016, 14, 9225
    DOI: 10.1039/C6OB01455K

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