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Taking Aim at Trypanosomes

February 2010

Chemical Genomics: Robot
The NIH Chemical Genomics Center (NCGC), administered by the National Human Genome Research Institute (NHGRI), is training its leading-edge technology on two ancient scourges: Chagas disease and African sleeping sickness.

In two studies published Nov. 11 in the online edition of the Journal of Medicinal Chemistry, NCGC researchers, along with collaborators from the University of California-San Francisco (UCSF), identified a group of compounds with the potential to inhibit parasitic Trypanosoma microbes and unveiled a public dataset that will aid the entire field of drug discovery.

Though microscopic in size, Trypanosoma take a very large toll on the health of people in the developing world. Spread by blood-sucking bugs, T. cruzi causes American trypanosomiasis, commonly called Chagas disease. About 16 million people, primarily in Latin America, are infected with the parasite. The chronic form of Chagas' disease can damage the heart, esophagus and peripheral nervous system. T. brucei, which is transmitted by tsetse flies, causes African trypanosomiasis, or African sleeping sickness. If untreated, the parasite migrates to the central nervous system, causing seizures, mental disorders and, ultimately, death. As many as 70,000 people are infected in Central and East Africa.

Current anti-trypanosomal therapies use two drugs, both of which can cause severe side effects and work only in the acute phase of the infection. The limited window for treatment, along with concerns about the development of drug-resistant parasites, has heightened the urgency for discovery of safe, effective and economical new drugs.

In 2005, NHGRI-supported researchers sequencing the genome of the insect, Rhodnius prolixus, that spreads the parasite that causes Chagas disease.

To help address the need for better drugs, the NCGC-USCF team designed an automated, high-throughput screen to search for chemical compounds that block cysteine proteases, a key group of enzymes that Trypanosoma microbes need to survive and reproduce. Specifically, the researchers screened NCGC's public catalog of 200,000 organic chemical compounds, dubbed small molecules, for previously unidentified inhibitors of the cruzain enzyme in T. cruzi and rhodesain and cathepsin B-like protease enzymes in T. brucei.

After analysis and validation of data, one class of compounds, triazine nitriles, stood out as possessing novel activity against the Trypanosoma cysteine proteases. In an effort to maximize this inhibitory power, medicinal chemists tweaked the chemical structure of these triazine nitriles, including swapping out a triazine with a purine in the compounds' core scaffolds. The result? A series of compounds with up to 350 times more power to inhibit key Trypanosoma enzymes in biochemical assays than the original triazine nitriles. In addition, the modified compounds demonstrated greater activity against live T. brucei parasites grown in laboratory culture.

"These novel and potent small molecule inhibitors represent an attractive starting point for the development of new drugs to help the millions of people around the globe who suffer from these devastating parasitic diseases," said NCGC Director Christopher Austin, M.D., a co-author of the papers and an associate investigator in NHGRI's Division of Intramural Research.

Along with the paper describing the identification of potential new drug candidates for American and African trypanosomiasis, the researchers published a companion paper detailing important lessons learned during the screening and analysis process. "This comprehensive and publically available profile of screening artifacts and interferences is the first of its kind for high-throughput screening. It will serve as an important dataset to guide interpretation of future screening results by all researchers in the drug development field," said Dr. Austin.

NCGC is an ultra-high-throughput screening and chemistry center, located in Rockville, Md., that discovers chemical probes of gene and cell functions to be used as biomedical research tools, or as starting points in the development of new therapeutics for rare and neglected diseases. NCGC collaborates with more than 100 researchers from academic, foundation and biopharmaceutical laboratories throughout the world. For more about NCGC, visit their Web site at www.ncgc.nih.gov.

Last updated: July 31, 2012