Collagen-Targeted Therapeutics of Cathepsin Inhibitors

描述(由申请人提供)：许多病理情况(如癌症、骨质疏松症、关节炎和纤维化)与由不同组的蛋白水解酶(如基质金属蛋白水解酶、丝氨酸蛋白酶和半胱氨酸水解酶)介导的过度胶原降解有关。其中，半胱氨酸蛋白酶被认为是最重要的治疗靶点之一，各种组织蛋白基因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ON和/或OFF靶细胞毒性(溶酶体效应)限制了这些潜在药物的临床应用，目前只有少数几种药物正在进行人体试验。鉴于最近发现组织蛋白酶在细胞外的活性与病理条件密切相关，将组织蛋白酶抑制剂定位到细胞外空间，特别是定位到正在进行降解活动的地方的能力，可能会使组织蛋白酶和其他蛋白酶抑制剂的临床应用取得突破。本项目将测试作为靶向病理组织中降解的胶原蛋白的药物递送剂的适合性，重点是开发新的胶原模拟多肽(CMP)和不可逆组织蛋白酶K抑制剂的合成结合物。这项拟议工作的总体目标是探索与开发抗吸收治疗药物有关的CMP介导的靶向能力和将不可逆组织蛋白酶K(Cat-K)抑制剂输送到正在降解的胶原蛋白的治疗益处。

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.