Development of New Hybrid-type Drugs Targeted to the Mechanism of Bone Remodeling

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The aim of this study is to develop newly drug molecules that act as bone resorption inhibitors and to make hybrid type drugs with new molecules and the pre-existed drugs or the delivery materials. The following results were obtained.・The newly developed small peptide, WP9QY, is the antagonist for the TNF-a receptor and shows the activity to inhibit osteoclast formation. WP9QY also inhibit enhanced bone resorption in the animal model such as the low calcium feeding rats, the ovaryectomy rats, the arthritis induced rats and the periodontitis bacteria injected rats. In addition, WP9QY has the anti-inflammatory effects.・Other than the antagonist for TNF-a receptor, WP9QY prevents the RANK-RANKL interaction and acts as an antagonist. WP9QY interferes the RANK-RANKL through its binding to the receptor-ligand complex and changing the conformation of the complex.・Newly synthesized peptide, NBD, blocks the movement of NF-kB to the nucleus and interferes the proliferation and differentiation of osteoclasts. It also shows the inhibitory effects on bone resorption in various animal model for bone resorption.・The hybrid molecule combined with CHP-nanogel and WP9QY peptide improves the stability of the peptide in the body and releases peptide slowly. The hybrid molecule inhibited bone resorption more efficiently than peptide itself in various animal model for bone resorption.Form these results, the new drugs that target the cytokine receptor or the signal transduction system in osteoclasts seems to contribute the development of therapeutic regimen for bone resorption inhibitors. Moreover the hybrid molecules with hydrogel scaffolds and new drugs improve the stability and efficacy of drugs and these hybrid molecules may serve as a more potent drugs that inhibit bone resorption.