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

针对骨重塑机制的新型混合型药物的开发

基本信息

批准号：
16209053
负责人：
OHYA Keiichi
金额：
$ 31.12万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209053/
关键词：
bone resorption periodontitis osteoclasts Rheumatoid Arthritis TNF RANKL Nano-gel Mini-pump RANK NF-kβ 骨粗鬆症

项目摘要

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.

本研究的目的是开发具有骨吸收抑制作用的新型药物分子，并将新分子与现有药物或给药材料制成杂交型药物。得到了以下结果。·新开发的小肽WP9QY是肿瘤坏死因子-α受体的拮抗剂，具有抑制破骨细胞形成的活性。对低钙喂养大鼠、卵巢切除大鼠、关节炎大鼠、牙周炎细菌注射大鼠等动物模型的骨吸收增强也有抑制作用。此外，WP9QY还具有抗炎作用。·WP9QY不是肿瘤坏死因子-α受体的拮抗剂，而是阻止RANK-RANKL相互作用的拮抗剂。WP9QY通过与受体-配体复合体结合并改变复合体的构象来干扰RANK-RANKL。·新合成的多肽NBD阻止了核因子-kB向细胞核的移动，并干扰了破骨细胞的增殖和分化。也显示了在不同的骨吸收动物模型中对骨吸收的抑制作用。·CHP-纳米凝胶与WP9QY多肽结合的杂化分子提高了多肽在体内的稳定性，并缓慢释放多肽。在不同的骨吸收动物模型中，杂化分子比多肽本身更有效地抑制骨吸收。因此，针对破骨细胞中细胞因子受体或信号转导系统的新药似乎有助于骨吸收抑制剂治疗方案的发展。此外，与水凝胶支架和新药结合的杂化分子提高了药物的稳定性和有效性，这些杂化分子可能成为更有效的抑制骨吸收的药物。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis

DOI：
10.1016/j.bone.2004.06.018
发表时间：
2004-11-01
期刊：
BONE
影响因子：
4.1
作者：
Nagahama, K;Aoki, K;Ohyama, K
通讯作者：
Ohyama, K

A TNF receptor loop peptide mimic blocks RANK liganda-induces signaling, bone resorption, and bone loss.

TNF 受体环肽模拟物可阻断 RANK 配体诱导的信号传导、骨吸收和骨丢失。

DOI：
发表时间：
2006
期刊：
The Journal of Clinical Investigation. 116(6)
影响因子：
0
作者：
Kitaichi N;Shimizu T;Honda A;Abe R;Ohgami K;Shiratori K;Shimizu H;Ohno S;Aoki K.
通讯作者：
Aoki K.

A TNF-α antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalls infection in mice.

TNF-α 拮抗剂可抑制小鼠牙龈卟啉单胞菌感染诱导的炎症性骨吸收。