Cysteine protease inhibitors as potential antiparasitic agents

Abstract

Parasitic cysteine proteases have attracted considerable attention, primarily due to their essential roles in the maintenance of cellular homeostatic processes such as metamorphosis and organogenesis. They also regulate host-parasite interactions by modulating a variety of pathobiological events, including host tissue degradation, nutrient uptake and immune evasion. The specific inhibition of these enzymes, by either immunoprophylaxis or chemotherapy, may potentially impair the survival mechanisms of the parasites. Therefore, these proteases are promising targets for vaccines or chemotherapeutics. To date, a number of cysteine protease inhibitors, including fluoromethyl ketone, heterocyclic oxygen-containing peptidomimetics, or vinyl sulfones, have been introduced and evaluated for protozoan infections. Pioneer studies of parasitic cysteine protease inhibitors have employed irreversible inhibitors. However, recent trends show a use of reversible inhibitors, largely owing to the potential harm of non-selective irreversible inhibitors. Several non-peptide inhibitors that exhibit more drug-like properties have recently been developed, through which protease-mediated degradation can be impeded in living systems. These non-peptide inhibitors also appear to reveal potential for high in vivo activity and selectivity against parasites. This review focuses on the current understanding of the actions and properties of parasitic cysteine proteases and describes advances in the development of specific inhibitors for cysteine proteases, largely based on cathepsins B and L, which may be useful in the development of novel antiparasitic agents.