Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas' disease, and leishmaniasis.
Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor alpha-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense sleeping sickness. Another ODC inhibitor, 3-aminooxy-1-aminopropane (APA), is considerably more effective than DFMO against Leishmania promastigotes and amastigotes multiplying in macrophages. AdoMetDC inhibitors can cure animals infected with isolates from patients with rhodesiense sleeping sickness and leishmaniasis, but have not been tested on humans. The antiparasitic effects of inhibitors of polyamine and trypanothione formation, reviewed here, emphasize the relevance of these enzymes as drug targets. By taking advantage of the differences in enzyme structure between parasite and host, it should be possible to design new drugs that can selectively kill the parasites.
Heby
O
O
Department of Molecular Biology, Umeå University, Umeå, Sweden. olle.heby@molbiol.umu.se
Persson
L
L
Rentala
M
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D015317:Biogenic Polyamines / Q000096:biosynthesis*; D014355:Chagas Disease / Q000188:drug therapy*; D000518:Eflornithine / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000378:metabolism; D007896:Leishmaniasis / Q000188:drug therapy*; D065108:Ornithine Decarboxylase Inhibitors; D012370:Robenidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013095:Spermidine / Q000031:analogs & derivatives / Q000378:metabolism; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014347:Trypanosoma brucei gambiense / Q000187:drug effects / Q000378:metabolism; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D015317:Biogenic Polyamines; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D014344:Trypanocidal Agents; C102850:bis((3-(aminoiminomethyl)phenyl)methylene)carbonimidic dihydrazide trihydrochloride; D012370:Robenidine; C027548:S-adenosyl-3-thio-1,8-diaminooctane; C044809:trypanothione; D011436:Spermidine Synthase; D012437:Adenosylmethionine Decarboxylase; D005978:Glutathione; D000241:Adenosine; D013095:Spermidine; D000518:Eflornithine