Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis. Issue 39 (4th August 2016)

• Record Type: Journal Article
• Authors: Amso, Zaid; Kowalczyk, Renata; Watson, Maureen; Park, Young-Eun; Callon, Karen E.; Musson, David S.; Cornish, Jillian; Brimble, Margaret A.
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 39(2016)
• Page Start: 9225
• Page End: 9238
• Publication Date: 2016-08-04
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c6ob01455k
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Replacement of serine at position 3 of preptin (1-16) with alanine increased the proliferation and matrix mineralisation of foetal cultures of primary rat osteoblasts in vitro . 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.