Flavoprotein structure and mechanism. 5. Trypanothione reductase and lipoamide dehydrogenase as targets for a structure-based drug design

Abstract

Trypanothione reductase (TR) is a flavoenzyme that has been found only in parasitic protozoa of the order Kinetoplastida. The enzyme catalyzes the NADPH-dependent reduction of glutathionylspermidine conjugates and is a key enzyme of the parasite's thiol metabolism. Consequently, TR is an attractive target molecule for a structure-based drug development against Chagas' disease, African sleeping sickness, and other diseases caused by trypanosomes and leishmanias. The three-dimensional structures of TR and of three enzyme substrate complexes have been solved. Several classes of compounds are discussed as guide structures for the design of specific inhibitors. Among them are tricyclic compounds such as acridines and phenothiazines, which competitively inhibit TR but not the related host enzyme glutathione reductase, as well as oxidase activity-inducing quinones and nitrofurans. Lipoamide dehydrogenase (LipDH) is another flavoprotein discussed as a target molecule for an antitrypanosomal therapy. In Trypanosoma cruzi, an organism that is highly susceptible to oxidative stress, LipDH participates in the redox cycling of nifurtimox, one of the most effective anti-Chagas agents. In conclusion, the structurally related enzymes TR and LipDH exhibit an unusually high one-electron-reducing capacity. Consequently, turncoat inhibitors and other compounds inducing an oxidase activity in both enzymes are promising drug candidates against Chagas' disease.