Biological thiol-dependent enzymes have recently received extensive attention in the literature because of their involvement in a variety of physiopathological conditions. The active thiol groups of these enzymes are derived from the cysteine residues present. Hence, in a biological system, the selective reversible or irreversible inhibition of the activity of these enzymes by modification of the thiol moiety may potentially lead to the development of a chemotherapeutic treatment. Despite all the research efforts involved in the attempt to develop potential chemotherapeutic treatments for the major diseases involving cysteine proteases, there are in fact no such treatments available yet. However, AG7088 (1) an inhibitor of rhinovirus-3C is in phase II/III clinical trial for the treatment of common cold and VX-740 (2, pralnacasan) an inhibitor of caspase-1 is in phase II clinical trial as an anti-inflammatory agent for rheumatoid arthritis. Several other cysteine protease inhibitors (i.e., cathepsin K, and S) are in pre-clinical evaluation or pre-clinical development. Structure-based drug design approaches have been instrumental in the development of these inhibitors. Intensive biochemical studies on the cysteine proteases have shed some light on some potential targets for therapeutic development. In addition, new techniques and new ideas are constantly emerging. As such, an up-to-date review of the literature on thiol-dependent enzymes as potential targets and their inhibitors designed from peptidic, modified peptidomimetic scaffolds and from small heterocyclic molecules is presented.
The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in beta-thalassemia and hereditary hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. Triapine is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical/clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with beta-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.
A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.
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