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.
The proposed work explores the benefit of delivering therapeutic drugs to collagens that are undergoing fast remodeling. The targeting is based on recently discovered peptide hybridization mechanism (discovered in PI's group) that is highly specific to denatured/degraded collagens which are found in a wide variety pathologic tissues (e.g. cancers, arthritis, fibrosis). In particular, a new type of drug for osteoporosis is proposed based on collagen-targeting enzyme inhibitors.
|Stahl, Patrick J; Chan, Tania R; Shen, Yu-I et al. (2014) Capillary Network-Like Organization of Endothelial Cells in PEGDA Scaffolds Encoded with Angiogenic Signals via Triple Helical Hybridization. Adv Funct Mater 24:3213-3225|