Drug Discovery and Human African Trypanosomiasis: A Disease Less Neglected?

Abstract

Human African trypanosomiasis (HAT) has been neglected for a long time. The most recent drug to treat this disease, eflornithine, was approved by the US FDA in 2000. Current treatments exhibit numerous problematic side effects and are often ineffective against the debilitating CNS resident stage of the disease. Fortunately, several partnerships and initiatives have been formed over the last 20 years in an effort to eradicate HAT, along with a number of other neglected diseases. This has led to an increasing number of foundations and research institutions that are currently working on the development of new drugs for HAT and tools with which to diagnose and treat patients. New biochemical pathways as therapeutic targets are emerging, accompanied by increasing numbers of new antitrypanosomal compound classes. The future looks promising that this collaborative approach will facilitate eagerly awaited breakthroughs in the treatment of HAT.

Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth

“…The phenomenon by which ergosterol can play dual roles in yeast has been defi ned as sterol synergism ( 26 ) and the two kinds of function, bulk and sparking, can be distinguished quantitatively from each other by differing sensitivities to the 24 ␤ -methyl group of the sterol's structure ( 31 ). Given the possibility that BSFs generate ergosterol in small amounts to promote growth and accessibility of very few therapeutic drugs, with many produced over 30 years ago, and toxicity issues ( 32,33 ), we examined the concentration dependence of ergosterol in T. brucei growth and evaluated the potential use of targeted enzymes of ergosterol biosynthesis for future therapies. Here we demonstrate that quantitative differences in the ergosterol content of PCFs or BSFs of different infective types contribute to variations in the growth response.…”

Phenolic Constituents of Medicinal Plants with Activity against Trypanosoma brucei

“…The Z 1 factor for the controls was calculated to be 0.64 using the equation defined as Z 1 = 1´3(σ C + + σ C´) /|µ C +´µ C´| where σ C + /σ C´a re the standard deviation (SD) of the positive/negative controls and µ C + /µ C´a re the mean values, indicating that the assay was performed with a sufficient window between the two controls ( Figure 1). [9,10]. Current clinical treatment relies on very few drugs, namely, suramin, pentamidine, melarsoprol and eflornithine (the latter now also in combination with nifurtimox) [11].…”

“…T. b. gambiense HAT takes a chronic course usually lasting for years, while T. b. rhodesiense HAT causes an acute course usually taking only months. Both forms inevitably lead to death if untreated [9,10]. Current clinical treatment relies on very few drugs, namely, suramin, pentamidine, melarsoprol and eflornithine (the latter now also in combination with nifurtimox) [11].…”

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines

“…[11][12][13] Increasingly, the search for novel antiprotozoal agents also involves the repositioning of existing drugs registered for other applications 14 or the synthesis of new chemical entities endowed with antiprotozoal activity. [15][16][17] In recent years, new compounds bearing the 4-amino-7-chloroquinoline core of chloroquine, or other aminoquinoline moieties, have been assessed as novel trypanocidal or antimalarial agents, or as dual agents endowed with both activities. [18][19][20][21] The development of single molecules that have potency against different protozoan diseases (such as HAT and malaria) has been regarded as an feasible approach, with potential economic savings.…”