State of the Art in African Trypanosome Drug Discovery

Abstract

African sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer. This breakthrough represents the only new therapy for HAT since the approval of eflornithine. A number of research programs are on going to exploit the unusual biochemical pathways in the parasite to identify new targets for target based drug discovery programs. HTS efforts are also underway to discover new chemical entities through whole organism screening approaches. A number of inhibitors with anti-trypanosomal activity have been identified by both approaches, but none of the programs are yet at the stage of identifying a preclinical candidate. This dire situation underscores the need for continued effort to identify new chemical agents for the treatment of HAT.

Chemical Composition and Trypanocidal Activity of the Essential Oils from Hedychium coronarium J. Koenig (Zingiberaceae)

“…The treatment with pentamidine is assumed to be the most effective in the acute infection but it can cause allergic and toxic side effects, most commonly affecting pancreas, with serious hypoglycemia, which, in part, depends on the daily and/or cumulative dose. In cases of brain impairment caused by the parasite, the condition may be irreversible [8]. Thus, there is an urgent need for the development of new effective and safe therapies for trypanosomiasis.…”

Deoxyhypusine Modification of Eukaryotic Translation Initiation Factor 5A (eIF5A) Is Essential for Trypanosoma brucei Growth and for Expression of Polyprolyl-containing Proteins

“…Human African trypanosomiasis, also known as sleeping sickness, is a fatal vector-borne disease caused by the single celled parasitic protozoan Trypanosoma brucei (1)(2)(3)(4). Although the disease reached epidemic levels in the 1990s, the World Health Organization now reports fewer than 10,000 cases, although millions in sub-Saharan Africa remain at risk (5).…”

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

“…HAT is endemic in over 36 countries and threatens over 60 million people within sub-Saharan Africa. Few drugs are available to treat HAT, and their use is complicated by limited efficacy that depends on both the subspecies and the development stage of the parasite (2,3). Treatment of late-stage disease is particularly problematic, and while the recent introduction of nifurtimox-eflornithine combination therapy (NECT) has improved treatment outcomes (4), more-effective drugs that combat all forms of the disease are still badly needed.…”