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 Tyr(10) 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 Tyr(10) amino group. No further loss occurred consequent to the monoiodination of desaminoTyr(10) on metaposition. However, a marked decrease in proliferative activity followed removal of the Tyr(10) phenolic or the Phe(12) aromatic group. Loss of activity of a similar magnitude also occurred subsequent to replacing Gly(11) with L- or D-Ala. Approximately 50% loss of mitogenic activity occurred subsequent to truncation of Gly(14) or blocking the C-terminal group as the methyl ester. All other modifications of the C-terminus and L- or D-Ala substitution of Gly(13) 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).