Use of cysteine-reactive small molecules in drug discovery for trypanosomal disease

The roles of cysteine protease (CP) enzymes in the biochemistry and infectivity of the three trypanosomal parasitic infections, Chagas' disease, leishmaniasis and human African trypanosomiasis, which have been elucidated over the last three decades are summarized. Inhibitors of these enzymes, which act through trapping the active site cysteine with an electrophilic warhead, hold huge potential as therapeutic agents but the promise of these has yet to be realized in clinical studies. The article addresses aspects that ought to be considered in order to develop orally active CP inhibitors that are safe and effective therapies for trypanosomiasis.

This article reviews learnings from CP research in the trypanosomal field and recent advances in developing cysteine protease inhibitors (CPIs) of human cathepsin K, a related enzyme. Considerations such as intra- and extracellular localization of the CPs, off-target activities against human cathepsin enzymes, basic versus neutral and potential pro-drug inhibitors are reviewed. A description of odanacatib, a cathepsin K inhibitor currently in late stage development, is made to illustrate the attributes of a clinically viable CPI.

The emerging role of CPs in a wide array of parasitic diseases is highlighted with the vision that CP inhibitors could become the 'β-lactams' of anti-parasitic treatments in the coming decades. New CPI research will see the optimization of intra- and extracellular enzyme targeting, reduction of off-target activities and better understanding of pharmacokinetic-pharmacodynamic interactions which will all lead to compounds with much improved efficacy and viability as clinical therapies.