The Battle against Trypanosomiasis and Leishmaniasis: Metal-based and Natural Product Inhibitors of Trypanothione Reductase

Trypanothione reductase is an enzyme that is unique to organisms belonging to the family Trypanosomatidae. Certain trypanosomatids, including trypanosomes and leishmania, are parasitic protozoa that are responsible for several devastating diseases. Trypanothione reductase plays a pivotal role in maintaining the redox balance of trypanosomatids, thus the development of inhibitors of trypanothione reductase may lead to the design of new drugs to combat diseases caused by parasitic trypanosomatids. Trypanothione reductase catalyzes the NADPH-mediated reduction of a glutathionespermidine conjugate named trypanothione. Several classes of trypanothione reductase inhibitors have been developed and discussed in recent reviews. However, less attention has focused on the interactions of inorganic compounds with trypanothione reductase. This is an intriguing area, since many of the current drugs used to treat trypanosomatid infections are metal-based complexes, containing either arsenic or antimony, and several of these compounds interact with trypanothione and/or trypanothione reductase. Thus, although the trypanocidal activities of these drugs involve several mechanisms, one site of action may be trypanothione reductase. In this review, the major diseases caused by Trypanosomatidae, current drugs, drug resistance, and an overview of trypanothione and trypanothione reductase are summarized. Recent work on the development of metal-based inhibitors of trypanothione reductase (including platinum(II) complexes) and interactions between certain inorganic compounds (including antimony(III), antimony(V) and arsenic(III) complexes) and trypanothione are discussed. Finally, studies of a range of natural products that inhibit trypanothione reductase are summarized.