Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Abstract

The general view on cysteine cathepsins, which were long believed to be primarily involved in intracellular protein turnover, has dramatically changed in last 10 to 15 years. The discovery of new cathepsins, such as cathepsins K, V, X, F and O, and their tissue distribution suggested that at least some of them are involved in very specific cellular processes. Moreover, gene ablation experiments revealed that cathepsins play a vital role in numerous physiological processes, such as antigen processing and presentation, bone remodelling, prohormone processing and wound healing. Their involvement in several pathologies, including osteoporosis, rheumatoid arthritis, osteoarthritis, bronchial asthma and cancer have also been confirmed and today several of them have been validated as relevant targets for therapies. Compounds targeting cathepsins S and K are already in clinical evaluation, whereas others are in experimental phases. The cathepsin K inhibitor AAE-581 (balicatib) as the most advanced of them passed Phase II clinical trials in 2005. In this review, we discuss the current view on cathepsins as an emerging group of targets for several diseases and the development of cathepsin K and S inhibitors for treatment of osteoporosis and various immune disorders.

Caught in the act: the crystal structure of cleaved cathepsin L bound to the active site of Cathepsin L

“…In addition to their role in endolysosomal protein degradation machinery, they participate in processes such as endosomal antigen presentation and are important regulators and signaling molecules of a large number of biological processes [2], such as thyroid hormone processing [3]. They are also involved in diseases, such as cancer and rheumatoid arthritis [4,5]. In contrast to other cysteine cathepsins with a rather uneven tissue-specific expression pattern, cathepsin L is ubiquitously expressed and thereby involved in large number of physiological processes, such as elastin degradation [6][7][8].…”

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect

“…(2)(3)(4)(5)(6)(7) Recent advances have led to the discovery of drugs that selectively inhibit either acid secretion (8)(9)(10) or catK activity. (2)(3)(4)(5)11,12) Some early catK inhibitors proved to have crossreactivity with other cathepsins, (5,13,14) and cutaneous adverse events were reported for one. (3,15) A highly selective catK inhibitor that affects osteoclast bone resorption activity without effects on other cell types, including osteoblasts, would be attractive as a treatment for osteoporosis.…”

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

“…The cathepsin family consists of cysteine, aspartate, and serine lysosomal proteases that play an important role in many physiological and pathological processes (Turk et al, 2000;Sloane et al, 2005;Mohamed and Sloane, 2006;Vasiljeva et al, 2007;Conus and Simon et al, 2008). Among these, cathepsin B is involved in the degradation of cellular proteins in lysosomes and functions as an endopeptidase at neutral pH.…”