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.

这项研究的目的是开发新开发的药物分子，这些药物是骨骼分辨率抑制剂的作用，并用新分子和现有的药物或递送材料制造混合型药物。获得以下结果。・新开发的小肽WP9QY是TNF-A受体的拮抗剂，并显示了抑制破骨细胞形成的活性。 WP9QY还抑制动物模型中的骨骼分辨率增强，例如低钙喂养大鼠，卵巢切除术大鼠，关节炎诱导的大鼠和细菌注入大鼠的牙周炎。此外，WP9QY具有抗炎作用。除了TNF-A受体的拮抗剂以外，WP9QY防止了等级秩相互作用，并充当拮抗剂。 WP9QY通过其与受体配体复合物的结合干扰了等级，并改变了络合物的构象。e新近合成的肽NBD阻断了NF-KB对核的运动，并干扰了骨质层的增殖和分化。它还显示了各种动物模型中骨骼分辨率的抑制作用。・混合分子与CHP-纳米凝胶和WP9QY肽结合，可改善肽在人体中的稳定性，并缓慢释放肽。在各种动物模型中，杂化分子比肽本身更有效地抑制骨骼的骨骼分辨率。预示着这些结果，靶向细胞因子受体或破骨细胞中信号转移系统的新药物似乎有助于开发用于骨修复抑制剂的治疗方案。此外，用水凝胶支架和新药的混合分子提高了药物的稳定性和效率，这些杂化分子可能是抑制骨修复的更潜在的药物。

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）

Subcutaneous Injections of a TNF-α Antagonistic Peptide Inhibit Both Inflammation and Bone Resorption in Collagen-Induced Murine Arthritis.

皮下注射 TNF-α 拮抗肽可抑制胶原诱导的小鼠关节炎的炎症和骨吸收。

DOI：
发表时间：
2005
期刊：
J Med Dent Sci 52・1
影响因子：
0
作者：
Kojima T.;Aoki K.;Amagasa T;et al.
通讯作者：
et al.

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。