Antiprotozoal Agents

Abstract

The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against T. brucei gambiense . Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in in vivo preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the N 1 , N 8 ‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.

Natural Products Active Against African Trypanosomes: A Step Towards New Drugs

“…Therefore, there is an urgent need for new molecules against sleeping sickness which are safe, effective, cheap and easy-to-administer and for new leads with novel mechanisms of action. [8][9][10][11] Nature with its numerous plants, microorganisms and marine organisms is a potential source of such new drugs since it contains a countless quantity of molecules with a great variety of structures and pharmacological activities. 12 Throughout the ages, mineral, plant and animal products have been the main sources of medicines for man.…”

Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog

“…Without treatment, the disease is always fatal. Current drug therapies are limited by toxicity and the requirement for complex treatment regimes (2). Polyamines are essential for cell growth in all organisms.…”

Gene Knockdown of γ-Glutamylcysteine Synthetase by RNAi in the Parasitic Protozoa Trypanosoma brucei Demonstrates That It Is an Essential Enzyme

“…Polyamine biosynthesis has been identified as a target for chemotherapeutic intervention against a number of proliferative diseases including African sleeping sickness (7)(8)(9). Unlike mammalian cells, trypanosomes conjugate the polyamine spermidine to GSH to generate a novel cofactor termed trypanothione (T(SH) 2 1 ; N 1 ,N 8 -bis(glutathionyl)spermidine; Fig.…”