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Scientists finds new drug target for malaria

Novartis and academics identify new class of medicines to treat all stages of infection
Novartis building

Researchers at Novartis and various academic institutions have identified a new class of drugs that -for the first time - promises to treat all stages of the malaria parasite's lifecycle in one hit.

The team - with funding from the US National Institutes of Health (NIH) - say they have identified a protein in Plasmodium parasites that is important for each stage of infection in the host and potentially could offer "an ideal activity profile for the prevention, treatment and elimination of malaria." Each year, malaria kills more than 660,000 people most of whom are African children.

The target is a lipid kinase called phosphatidylinositol-4-OH kinase or PI(4)K and can be inhibited by a dug class known as the imidazopyrazines, according to Novartis.

When a Plasmodium-carrying mosquito bites a human, it transmits infectious parasites that travel to the liver, where they multiply and mature, and then spread throughout the bloodstream, causing malaria symptoms to develop.

The team - led by Elizabeth Winzeler of the University of California, San Diego, and the Novartis Research Foundation - administered imidazopyrazines to mice and nonhuman primates infected with Plasmodium and found that the compounds blocked the parasites' development both in the liver and in the bloodstream stages of infection.

Currently only one drug - the elderly compound primaquine - has been approved for elimination of liver-stage parasites in malaria. It is recommended for use alongside artemisinin-based combination therapies (ACT), which remain the drug of choice but are starting to succumb to resistance in some areas of the world such as Southeast Asia.

With resistance emerging to the best-available therapy there is an urgent need for a new generation of treatments, and the imidazopyrazines could help plug the gap, according to Thierry Diagana, head of the Novartis Institute for Tropical Diseases.

Some forms of malaria - notably Plasmodium vivax - can become dormant in the liver only to re-emerge up to two years later and re-activate a blood-stage infection.

Novartis is also developing two other antimalarials in its pipeline, namely the spironolactone derivative KAE609 and imidazolopiperazine KAF156, which are currently in phase II testing.

Other drugs coming through development include GlaxoSmithKline's tafenoquine and Sanofi's OZ439 - both of which are aminoquinolines in phase II trials - and triazolopyrimidine candidate DSM265, which is being guided through phase I trials by an academic consortium.

Meanwhile, after years of disappointing trials vaccines for malaria are starting to make progress, with GSK hoping to file its RTS,S/AS01 candidate for approval next year despite modest efficacy. In August NIV researchers said they had achieved "unprecedented" results in a small study of a weakened, live Plasmodium falciparum vaccine called PfSPZ.

Article by
Phil Taylor

28th November 2013

From: Research

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