Uptake and mode of action of drugs used against sleeping sickness

Sleeping sickness is resurgent in Africa. Adverse side-effects and drug-resistance are undermining the few drugs currently licensed for use against this disease, which is caused by parasitic protozoa of the Trypanosoma brucei group. Pentamidine and suramin are used before parasites become manifest in the central nervous system, after which the organic arsenical melarsoprol is used. Eflornithine is also useful in late-stage disease. A mode of action has been elucidated only for the ornithine decarboxylase inhibitor eflornithine. Both uptake and potential intracellular targets need to be considered when contemplating modes of action. The melaminophenyl arsenicals are accumulated via an unusual amino-purine transporter termed P2, which also seems to have a role in the uptake of the diamidine class of drugs to which pentamidine belongs. Since loss of this transporter leads to drug-resistance, other uptake mechanisms also need to be considered in generating novel trypanocides. Some nitroheterocyclic drugs have prolific activity against trypanosomes, although the fact that they are mutagenic in Ames' tests is acting as a barrier to further development. New drugs are urgently needed and the advent of genome sequencing and target validation using genetic modification will hopefully accelerate this process. (C) 2000 Elsevier Science Inc. All rights reserved.