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Back to basics
LA JOLLA, Calif.–– An international team led by scientists from the Scripps Research Institute, the Swiss Tropical Institute, the Genomics Institute of the Novartis Research Foundation (GNF) and the Novartis Institute for Tropical Diseases has discovered a drug candidate that represents a potentially new class of drugs to treat malaria.
According to one of the lead researchers, this drug candidate was advanced as the result of a simple cell-based screening process, rather than more advanced medical research measures.
Clinical trials for the compound are planned for later this year.
"We're very excited by the new compound," says Elizabeth Winzeler, a Scripps Research associate professor and member of the GNF. "It has a lot of encouraging features as a drug candidate, including an attractive safety profile and potential treatment in a single oral dose."
Winzeler says this is her first experience with developing a promising drug candidate. She also indicated that the simple scientific method used in the research—a classic evolution study of generations of genes—was employed to drill down into the action of a specific compound within a parasite cell.
Rather than be closer to a cure after a century of work toward its eradication, the parasitic affliction malaria seems to be digging in. It is transmitted through infected mosquitoes that inject upon their bites the Plasmodium parasite. Malaria is endemic in some of the poorest parts of the world, including large swaths of the African continent, and the disease disproportionately impacts children and pregnant women.
Conversely, the need for new treatments is great, but little economic incentive exists to find one.
According to Winzeler, this disparity became more pronounced in the 1990s, when chloroquine lost its efficacy as an antimalarial, and the corresponding result was an explosion of malaria cases is Africa.
Winzeler has been pondering this problem for many years, and first began on the path to this recent development about seven years ago. After some initial slow progress, she and her team of scientists decided to pursue cell-based screening, a basic, tried-and-true approach in the development of new therapies.
She says a partnership with Novartis evolved in 2005, and in 2006, the research received support from Medicines for Malaria Venture and the Wellcome Trust.
After developing and using a high-throughput screen to identify compounds active against the malaria parasite Plasmodium falciparum, Novartis offered its extensive library of purified natural products. Winzeler led the research process with Thierry Diagana of the Novartis Institute of Tropical Diseases.
From the first screen, which turned up 275 compounds with anti-malarial activity, down to the final pass, which left 17 compounds in the running, Winzeler and her team were looking for a class of chemicals perhaps overlooked before.
The research involved labs in San Diego and Singapore, among others.
One compound stood apart from the small pack. Spiroindolones, a chemical in a class of molecules that had never been sought after for anti-malarial punch, looked like it held promise.
Additional work was done to make and study spiroindolone derivatives to find the safest and strongest candidates. After additional testing at the Swiss Tropical and Public Health Institute, NITD609 crossed the finish line as the most likely to succeed in trials.
Winzeler, who says she was more interested in looking at drug resistance as opposed to looking for targets, decided that she would look for single-base changes in drug-exposed genomes.
This method, she says, diffuses the traditional criticism of the chemistry community that research is flying blind in not knowing what target is being sought first.
As is more eloquently described by the researchers in an article in the Sept. 3 issue of Science, an experiment was conducted in which Winzeler's GNF colleague Case McNamara cloned a Plasmodium falciparum parasite and cultured each separately: one in a regular culture, and another with a small amount of the potential drug candidate.
The NITD609-spiked culture, over time, hosted parasites that began to demonstrate drug resistance. And when the researchers further examined the many generations of the two groups of organisms, only a few genetic mutations were observed.
The end result was the identification of one gene, PfATP4 as a target. The protein PfATP4 could then be the target, or could be part of the puzzle in another way.
"We haven't done the definitive experiment to identify PfATP4 as the target yet. PfATP4 is indicated by what we now know—that it might work," Winzeler explains. "It's a class of targets that makes sense."
The Scripps Research Institute is one of the world's largest independent, nonprofit biomedical research organizations and seeks to utilize basic biomedical science to comprehend the most fundamental processes of life.
Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular and infectious diseases and synthetic vaccine development. It was established in its current configuration in 1961 and employs approximately 3,000.