Structure-bioactivity of C-terminal pentapeptide of osteogenic growth peptide [OGP(10-14)].
The amino acid sequence of osteogenic growth peptide (OGP) consists of 14 residues identical to the C-terminal tail of histone H4. Native and synthetic OGP are mitogenic to osteoblastic and fibroblastic cells and enhance osteogenesis and hematopoiesis in vivo. The C-terminal truncated pentapeptide of OGP, H-Tyr-Gly-Phe-Gly-Gly-OH [OGP(10-14)], is a naturally occurring osteoblastic mitogen, equipotent to OGP. The present study assesses the role of individual amino acid residues and side chains in the OGP(10-14) mitogenic activity which showed a very high correlation between osteoblastic and fibroblastic cell cultures. Truncation of either Tyr10 or its replacement by Ala or D-Ala resulted in substantial, but not complete, loss of activity. Nevertheless, only a small loss of activity was observed following removal of the Tyr10 amino group. No further loss occurred consequent to the monoiodination of desaminoTyr10 on meta-position. However, a marked decrease in proliferative activity followed removal of the Tyr10 phenolic or the Phe12 aromatic group. Loss of activity of a similar magnitude also occurred subsequent to replacing Gly11 with L- or D-Ala. Approximately 50% loss of mitogenic activity occurred subsequent to truncation of Gly14 or blocking the C-terminal group as the methyl ester. All other modifications of the C-terminus and L- or D-Ala substitution of Gly13 resulted in 70-97% decrease in activity. Collectively, these data suggest that the integrity of the pharmacophores presented by Tyr and Phe side chains, as well as the Gly residues at the C-terminus, are important for optimal bioactivity of OGP(10-14).
Chen
Y C
YC
Bone Laboratory, Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel. babi@cc.huji.ac.il
Bab
I
I
Mansur
N
N
Muhlrad
A
A
Shteyer
A
A
Namdar-Attar
M
M
Gavish
H
H
Vidson
M
M
Chorev
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006133:Growth Substances / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D006133:Growth Substances; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C074533:osteogenic growth peptide