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Novartis compounds treat malaria in blood and liver

New class of antimalarial compound discovered by pharma company

Researchers at Novartis and academic organisations have discovered a new class of antimalarial compounds that appear to tackle not only the blood-borne phase of the parasites lifecycle, but also the hard-to-treat liver phase.

The Plasmodium species responsible for malaria is transmitted by infected mosquito bites, with the parasite injected into the blood stream and migrating to the liver where they infect cells and multiply. Once this phase of the lifecycle is complete the parasites are released back into the blood, ready for transmission to a new host.

The dual-acting imidazolopiperazines (IZPs) discovered by the team attack the parasite at both stages in its reproduction cycle, say the researchers, who have published their findings in the journal Science. That gives the class a much better chance of eradicating the infection, they note.

In some patients, the malaria parasite can lie dormant in the liver for months or years, allowing the disease to re-establish itself later.

Most currently-used drugs only attack the blood stages of the infection, and those that do exert some liver activity tend to be associated with significant side effects which restrict their use.

Moreover, there is a critical need for new malaria drugs in the face of emerging resistance even to the most effective artemisinin-based combination therapy (ACT) which was first encountered in southeast Asia  a couple of years ago. Improper storage of medicines, rampant diversion and counterfeiting are all thought to contribute to antimalarial resistance.

The scientists developed a novel assay to determine liver stage activity of candidate small molecules, and then used the assay and other tools to identify and optimise a chemical scaffold with activity on both blood- and liver-stage parasites in malaria mouse models.

They came up with the IZP class, which has the benefit of being orally bioavailable, and also protected healthy mice from developing the liver cycle of the parasite when administered at a dose of 15mg/kg. Novartis said it plans to start clinical trials of the lead candidate in the IZP class next year.

The research was conducted by scientists at the Novartis Institutes for BioMedical Research (NIBR), NIBR's Genomics Institute of the Novartis Research Foundation (GNF) and the Novartis Institute for Tropical Diseases (NITD), in collaboration with the Scripps Research Institute and Swiss Tropical and Public Health Institute.

This is the second new antimalarial class discovered by the team. Last September, they came up with a new spiroindolone class, led by the compound NITD609, on the back of a screening exercise involving a 12,000-strong compound library. That compound has now advanced into phase I testing.

Even with the current level of access to effective medicines, malaria affects 250 million people a year around the world and kills one million.

Mark Fishman, president of the NIBR, said that the chemical data from the latest study and the methods of chemical analysis have been released to the public domain "to facilitate broad-based discovery efforts across the globe towards elimination of this disease."

18th November 2011

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