Uptake and mode of action of drugs used against sleeping sickness

Sleeping sickness is resurgent in Africa. Adverse side-effects and drug-res istance are undermining the few drugs currently licensed for use against th is disease, which is caused by parasitic protozoa of the Trypanosoma brucei group. Pentamidine and suramin are used before parasites become manifest i n the central nervous system, after which the organic arsenical melarsoprol is used. Eflornithine is also useful in late-stage disease. A mode of acti on has been elucidated only for the ornithine decarboxylase inhibitor eflor nithine. Both uptake and potential intracellular targets need to be conside red when contemplating modes of action. The melaminophenyl arsenicals are a ccumulated via an unusual amino-purine transporter termed P2, which also se ems to have a role in the uptake of the diamidine class of drugs to which p entamidine belongs. Since loss of this transporter leads to drug-resistance , other uptake mechanisms also need to be considered in generating novel tr ypanocides. Some nitroheterocyclic drugs have prolific activity against try panosomes, although the fact that they are mutagenic in Ames' tests is acti ng as a barrier to further development. New drugs are urgently needed and t he advent of genome sequencing and target validation using genetic modifica tion will hopefully accelerate this process. (C) 2000 Elsevier Science Inc. All rights reserved.