Discovery and preclinical HAT projects: some examples
"Discovery" is the very first chapter in the research and development of a new drug, where the goal is to find the seed of a future medicine by screening thousands of chemical or natural compounds for their effect against a disease-causing parasite. The hope is to find one that kills the bug without harming the patient.
Screening at Kitasato
In April 2005 DNDi started a joint screening project with the Kitasato Institute, Japan, to identify compounds active against the trypanosome parasite that causes sleeping sickness. Drawing on Kitasato’s vast experience and expertise in the field of infectious disease, the project screens natural substances from the Kitasato library, and other universities, e.g., samples collected from the soil, traditional Japanese and Chinese herbal medicines or plant extracts.
The first achievement of the DNDi-Kitasato project was the establishment of an in vitro assay with trypanosomes to screen compounds for their capacity to kill the parasites. To acquire the necessary scientific know-how, a researcher from the Kitasato Research Center for Tropical Diseases was trained at the Swiss Tropical Institute (STI). Upon her return she tried to establish the assay in her laboratory, but this was not as easy as expected. The standard strain necessary for the assay was not available in Japan; importing one from STI took several months and required tons of paper work. When some reference compounds were screened, there was a yawning chasm between the results obtained at Kitasato and those from STI. Adjusting strains to the Japanese environment was just as difficult as it is for Europeans to adjust to Japanese culture!
After months of repeated trial and error, the researchers finally established the assay called a long incubation-low inoculation test (LILIT). In this assay, pre-diluted test samples and Trypanosoma parasites are incubated for 72 hours. After incubation, the anti-trypanosomal activity of each sample is evaluated by a fluorometric assay. Effective compounds are tested for toxicity, and only compounds that are safe and effective will be evaluated further. The goal is to find a compound that is effective in an animal model of sleeping sickness.
By now, almost 10,000 samples have been screened and a few of them have been found highly active against the target parasite. For the coming years, DNDi and Kitasato are planning to proceed with the identified hits to conduct in vivo screening and lead compound optimization in the hope of finding a new treatment for Human African Trypanosomiasis.
DNDi Liaison Japan
The enzyme trypanothione reductase (TR) has been genetically validated as essential for growth and survival of trypanosomes and leishmania. Thus, TR inhibitors are a potential drug target to treat human African trypanosomiasis, leishmaniasis, and Chagas disease.
The purpose of DNDi’s TR inhibitors programme, performed at the University of Dundee under the supervision of Prof Alan Fairlamb, is to identify new drug-like molecules through high throughput screening against trypanothione reductase. The initial phase allowed the identification of promising lead chemical structures active against the target enzyme. In the next phase, medicinal chemistry will continue to obtain new chemical analogues with higher selectivity and potency against the enzyme.
Project Manager DNDi
Compound mining: New and old nitroimidazoles
Cysteine protease inhibitors
Cysteine proteases are a family of enzymes that degrade specific proteins both as part of the normal turnover of proteins in parasites and as part of their invasive armoury for attacking the host. Jim McKerrow and his team at the UCSF have taken two different approaches to validate these enzymes as drug targets in T. brucei, the causative agent of human African sleeping sickness.
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