title: Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis.
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.
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland 1142, New Zealand. m.brimble@auckland.ac.nz.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Amso
authors.forename: Renata
authors.initials: R
authors.lastname: Kowalczyk
authors.forename: Maureen
authors.initials: M
authors.lastname: Watson
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Park
authors.forename: Karen E
authors.initials: KE
authors.lastname: Callon
authors.forename: David S
authors.initials: DS
authors.lastname: Musson
authors.forename: Jillian
authors.initials: J
authors.lastname: Cornish
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
mesh_terms: D000595:Amino Acid Sequence; D045930:Anabolic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D007335:Insulin-Like Growth Factor II / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D055550:Protein Stability; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D045930:Anabolic Agents; D010446:Peptide Fragments; C443100:preptin; D007335:Insulin-Like Growth Factor II