Collagen-Targeted Therapeutics of Cathepsin Inhibitors

描述（由申请人提供）：许多病理状况（如癌症、骨质疏松、关节炎和纤维化）与不同的蛋白酶（如基质金属蛋白酶（MMP）、丝氨酸蛋白酶和半胱氨酸蛋白酶）介导的过多胶原降解有关。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，各种组织蛋白酶敲除小鼠模型都证明了这一点。尽管已经开发了20多种不同类型的组织蛋白酶抑制剂，但它们的靶向和/或脱靶细胞毒性（溶酶体促性作用）限制了这些潜在药物的临床应用，目前只有少数药物正在进行人体试验。鉴于最近的研究发现，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到细胞外空间的能力，特别是降解活性正在进行的地方，可能会导致组织蛋白酶和其他蛋白酶抑制剂在临床应用方面取得突破。该项目将测试CMP作为靶向病理组织中降解胶原的药物递送剂的适用性，重点是开发新的合成胶原模拟肽（CMP）和不可逆组织蛋白酶K抑制剂的偶联物。拟议工作的总体目标是探索CMP介导的靶向能力和向正在降解的胶原提供不可逆组织蛋白酶K （Cat-K）抑制剂的治疗益处，这与开发抗骨质疏松症再吸收治疗药物有关。

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.