Collagen-Targeted Therapeutics of Cathepsin Inhibitors

组织蛋白酶抑制剂的胶原蛋白靶向治疗

基本信息

批准号：
8771219
负责人：
Michael S Yu
金额：
$ 21.26万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771219
关键词：
Acids Animal Model Arthritis Atherosclerosis Binding Biodistribution Bone Resorption Caspase Cathepsins Cells Characteristics Chelating Agents Chondrogenic Neoplasm Clinical Collagen Cysteine Cysteine Protease DEXA DNA Folding Disease susceptibility Drug Delivery Systems Drug Kinetics Drug Targeting Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Estradiol Evaluation Extracellular Matrix Extracellular Space Felis catus Fibroblasts Fibrosis Gel Gelatin Heating Human Hydroxyproline Image In Vitro Knockout Mice Label Lead Light Link Location Malignant Neoplasms Marketing Matrix Metalloproteinases Mediating Metalloproteases Modeling Molecular Mus Osteoclasts Osteoporosis Ovariectomy Pathologic Peptide Hydrolases Peptides Pharmaceutical Preparations Phenotype Prednisone Protease Inhibitor Proteins Protocols documentation Radio Radioactivity Reporting Scanning Serine Protease Serum Signal Pathway Specificity Staining method Stains Structure Testing Therapeutic Therapeutic Agents Tissues Toxic effect Work articular cartilage base bone cathepsin K cellular targeting clinical application clinically relevant glycylproline humanized antibody in vivo inhibitor/antagonist innovation melting mimetics mouse model optical imaging public health relevance research study single photon emission computed tomography skeletal tissue therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): Numerous pathologic conditions (e.g. cancer, osteoporosis, arthritis, and fibrosis) are associated with excess collagen degradation mediated by distinct sets of proteases such as matrix metalloproteases (MMP), serine proteases, and cysteine proteases. Among them, cysteine cathepsins (cystein proteases) are considered one of the most important therapeutic targets as evidenced by various cathepsin knockout mice models. Although over 20 different types of cathepsin inhibitors have been developed, their on and/or off target cellular toxicity (lysosomotropic effect) has limited clinical use of these potenial drugs, and only a few are currently undergoing human trials. In light of recent findings that cathepsin's activity outside the cells are strongly associated with pathologic conditions, the ability to localize cathepsin inhibitor to extracellular spaces, in particular, to places where degradative activity is ongoing could lead to a breakthrough in clinical application of cathepsin and other protease inhibitors. This project will test the suitability of CMP as drug delivery agent for targeting degrading collagens in pathologic tissues, with particular focus on developing new synthetic conjugates of collagen mimetic peptide (CMP) and irreversible cathepsin K inhibitor. Overall objective of the proposed work is to explore the CMP mediated targeting capacity and therapeutic benefits of delivering irreversible cathepsin K (Cat-K) inhibitors to collagens undergoing degradation as related to developing anti-resorptive therapeutic agents for osteoporosis.

描述（由申请人提供）：许多病理疾病（例如癌症，骨质疏松，关节炎和纤维化）与多种蛋白酶（如甲状化蛋白酶（MMP），丝氨酸蛋白酶），丝氨酸蛋白酶和细胞蛋白酶蛋白酶介导的过量胶原蛋白降解有关。其中，半胱氨酸组织蛋白酶（Cystein蛋白酶）被认为是最重要的治疗靶标之一，这是各种组织蛋白酶基因敲除小鼠模型所证明的。尽管已经开发了20多种不同类型的组织蛋白酶抑制剂，但它们的ON和/或关闭靶细胞毒性（溶酶体效应）的临床用途有限，目前只有少数正在接受人体试验。鉴于最近发现细胞以外的组织的活性与病理状况密切相关，即将组织蛋白酶抑制剂定位到细胞外空间，特别是在持续降解活性的地方可能导致在临床应用中临床应用和其他蛋白酶抑制剂的突破。该项目将测试CMP作为药物输送剂的适用性，以靶向病理组织中降解胶原蛋白，尤其着重于开发新的胶原蛋白模拟肽（CMP）的合成偶联物（CMP）和脱离的组织蛋白酶抑制剂。拟议工作的总体目的是探索CMP介导的靶向能力和治疗益处，可将不可逆的组织蛋白酶K（CAT-K）抑制剂提供给胶原蛋白，这与开发抗强化治疗剂有关的胶原蛋白，以降解骨质疏松剂。