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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）：许多病理状况（例如癌症、骨质疏松症、关节炎和纤维化）与不同蛋白酶组（例如基质金属蛋白酶（MMP）、丝氨酸蛋白酶和半胱氨酸蛋白酶）介导的过度胶原降解相关。其中，半胱氨酸组织蛋白酶（半胱氨酸蛋白酶）被认为是最重要的治疗靶点之一，如各种组织蛋白酶敲除小鼠模型所证明的。尽管已经开发了超过20种不同类型的组织蛋白酶抑制剂，但它们的靶细胞毒性（亲溶酶体作用）限制了这些潜在药物的临床使用，并且目前只有少数正在进行人体试验。鉴于最近发现组织蛋白酶在细胞外的活性与病理状况密切相关，将组织蛋白酶抑制剂定位于细胞外空间，特别是降解活性正在进行的地方的能力可能导致组织蛋白酶和其他蛋白酶抑制剂的临床应用的突破。本项目将测试CMP作为靶向降解病理组织中胶原的药物递送剂的适用性，特别关注开发新的胶原模拟肽（CMP）和不可逆组织蛋白酶K抑制剂的合成缀合物。拟议工作的总体目标是探索CMP介导的靶向能力和将不可逆的组织蛋白酶K（Cat-K）抑制剂递送至正在降解的胶原蛋白的治疗益处，这与开发骨质疏松症的抗吸收治疗剂有关。