Trypanothione reductase: a viable chemotherapeutic target for antitrypanosomal and antileishmanial drug design

Abstract

Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed.

Keywords: Chagas disease; Trypanothione; glutathione; rational drug design; sleeping sickness.

Figure 1

Structures of the currently available drugs for the treatment of trypanosomiasis and leishmaniasis.

Figure 2

Metabolism and function of trypanothione, showing possible sites of action of trypanocidal compounds. The insert above illustrates the futile redox cycling by nitro compounds (RNO₂) to form hydrogen peroxide (H₂O₂) and hydroxyl radicals (OH^•). Abbreviations: BSO, buthionine sulfoximine; DFMO, difluoromethylornithine; R-As=O, melarsen oxide; Mel T, melarsen trypanothione adduct; PUT, putrescine; SPD, spermidine; dSAM, decarboxylated S-adenosylmethionine; MTA, methylthioadenosine (modified from Krauth-Siegel et al. 1987).

Figure 3

Outline of glutathione and trypanothione based redox defences.

Figure 4

Structure of trypanothione reductase with FAD, NADPH and trypanothione bound (modified from Bond et al. 1999).

Figure 5

Structures and activities of tricyclic inhibitors of trypanothione reductase.

Figure 6

Structures of 2-aminodiphenylsulfides with their anti-TR activities.

Figure 7

Structures of quaternary alkylammonium compounds with their anti-TR activities.

Figure 8

Compound 18 docked into active site of TR to show major interactions (taken from Austin et al. 1999).

Figure 9

Structures and trypanothione reductase inhibitory activities of polyamine derivatives.

Figure 10

Bisbenzyleisoquinoline alkaloid.

Figure 11

The natural product inhibitors of trypanothione reductase.

Figure 12

Structures of irreversible inhibitors of trypanothione reductase.

Figure 13

Proposed reaction mechanisms for the modification of protein thiol (RSH), e.g. Cys52 in T. cruzi trypanothione reductase by an unsaturated Mannic base such as 30 (Modified from Lee et al. 2005).

Figure 14

Structures and activity of subversive substrates of trypanothione reductase.

Scheme 1

Glutathion and trypanothione.