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Osteogenic growth peptide: from concept to drug design.

Recently, the osteogenic growth peptide (OGP) and its C-terminal pentapeptide H-Tyr-Gly-Phe-Gly-Gly-OH [OGP(10-14)] have attracted considerable clinical interest as bone anabolic agents and hematopoietic stimulators. They are present in mammalian serum in micromolar concentrations, increase bone formation and trabecular bone density, and stimulate fracture healing when administered to mice and rats. In cultures of osteoblastic and other bone marrow stromal cells, derived from human and other mammalian species, OGP regulates proliferation, alkaline phosphatase activity and matrix mineralization via an autocrine/paracrine mechanism. In vivo it also regulates the expression of type I collagen and the receptor for basic fibroblast growth factor. In addition, OGP and OGP(10-14) enhance hematopoiesis, including the stimulation of bone marrow transplant engraftment and hematopoietic regeneration after ablative chemotherapy. Apparently, the hematopoietic effects of these peptides are secondary to their effect on the bone marrow stroma. Detailed structure-activity relationship study identified the side chains of Tyr(10) and Phe(12) as the principal pharmacophores for OGP-like activity. Recently, it has been demonstrated that several cyclostereoisomers of OGP(10-14), including the analogue retro-inverso (Gly-Gly-D-Phe-Gly-D-Tyr), share the full spectrum of OGP-like bioactivities. Taken together, OGP represents an interesting case of a "housekeeping" peptide that plays an important role in osteogenesis and hematopoiesis, and interacts with its putative macromolecular target via distinct pharmacophores presented in a specific spatial organization.