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.