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Free Content Editorial [Hot topic: The Medicinal Chemistry of the Cathepsin Cysteine Proteases (Guest Editors: Keiichi Masuya and Naoki Teno)]

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The catalytic site of cathepsin cysteine proteases is located within the binding region which has subsites for substrate amino acids in both the N- and C-terminal direction from the scissile bond. The catalytic site is highly conserved and formed by three residues: Cys, His and Asn. The crucial step of the catalytic process involves formation of a reactive thiolate/imidazolium ion pair, which results from proton transfer between Cys and His, resulting in forming an active Cys residue. In most cases, the development of selective cathepsin inhibitors is moving forward on the basis of: information on the subsites for substrate amino acids, and the warhead which binds to a thiol group of the active center of cathepsins.

The various reversible or irreversible cathepsin inhibitors, which were designed over the past 15 years, underscore the importance of inactivation of the cathepsins which are involved in particular diseases. In this special issue of Current Topics in Medicinal Chemistry with the title “The Medicinal Chemistry of the Cathepsin Cysteine Proteases”, the authors provide refined reviews that give a critical update on the current understanding and advance of the medicinal chemistry on the selective cathepsins C, S and K inhibitors developed by many institutes.

The human cysteine cathepsin family comprises 11 genes (cathepsins B, C, H, F, K, L, O, S, V, W, and X/Z). Since some of cathepsins are implicated in many physiological processes such as protein degradation, antigen presentation, bone resorption, we now understand how important a role of cathepsins play. Additionally, it has been found that some cathepsins are involved in a number of degradative and invasive processes such as arthritis, tumor invasion and metastasis and muscular dystrophy as well. There exists a discrepancy in the physiological processes that arise from the primary, secondary and tertiary structures of each cathepsin. The understanding of tertiary structure of target enzymes has especially provided a wealth of information to help speed up drug discovery research and bring newer and better therapies to the market place. Tomoo elaborates recent advances in structure of cathepsins B, K, L and S, and also provides a thorough overview of structural features of cathepsins and his approach in structure-based design of cathepsin B specific inhibitors.

Like other cysteine proteases cathepsin C is involved in intracellular protein degradation even though the enzyme is the noted exception, existing as an oligomeric enzyme with a molecular weight of 200kDa. Cathepsin C is the physiological activator of groups of serine proteases within immune and inflammatory cells that are vital for the defense of an organism. Percival et al. discuss the therapeutic utility and recent progress in medicinal chemistry of cathepsin C inhibitors.

Current marketed therapies for neuropathic pain are based largely on two well established classes: the analgesics opiates and the nonsteroidal anti-inflammatory drugs. Both classes of drugs have limited efficacy and evoke undesirable side effects. The lack of suitable therapies has stimulated research regarding target identification for neuropathic pain. It has been reported that the mRNA encoding cathepsin S was up-regulated in rat dorsal root ganglia following peripheral nerve injury. Cathepsin S is expressed in professional antigen presentation cells such as dendritic cells, B lymphocytes, and macrophages. Hence, the major role of cathepsin S in these cells is in the important proteolytic events that lead to antigen presentation. Cathepsin S inhibitors are thus being developed as immunological therapeutic agents. Wiener et al. review the recent advance in the various peptidic and non-peptidic cathepsin S inhibitors using the structure activity relationship both with and without warhead.

Since the discovery of the cysteine protease cathepsin K, many studies have shown that this enzyme is of importance in bone resorption. Kometani et al. provide insights into the hurdles in the drug discovery of cathepsin K inhibitors for the treatment of bone resorption. Odanacatib is the most advanced cathepsin K inhibitor for which the phase III study is currently proceeding to treat post-menopausal osteoporosis. Black discusses the design of Odanacatib and peptidic and non-peptidic analogs derived from Odanacatib. Teno et al. review small molecule non-peptidic inhibitors possessing pyrrolopyrimidine as a new scaffold for cathepsin K.
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Document Type: Research Article

Affiliations: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Werk Klybeck Postfach, CH-4002 Basel, Switzerland.

Publication date: May 1, 2010

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