New malaria drug candidate could cure in a single dose.

Abstract

A brand new synthetic antimalarial drag candidate has shown spectacular activity in mice, and could lead to Phase 1 trials in humans next year. A dose of the molecule cut mouse malaria parasitaemias extremely rapidly, as quickly as artemisinin--the current record-holder. But whereas artemisinin and its let the malaria parasite grow back within a few days, requiring more doses of the drug or additional drugs in combination, the new peroxide kept the parasites down for more than 60 days with just a single dose. It's quite remarkable and doesn't quite fit with the pharmacokinetics [the way the drug moves through the animal] but we are working on that to put the pieces together to understand how working, John Vennerstrom of the University of Nebraska, leader of the international research team that created the drug, told the Bulletin. In June the Medicines for Malaria Venture (MMV), a public-private partnership, picked this as the most promising research funded by MMV over the past year. Simon Campbell, former Head of Worldwide Discovery at Pfizer, who chairs the MMV Expert Scientific Advisory Committee said group took the well-established antimalarial `warhead' found in artemisinin and developed it into a chemical series that is now very drug-like and amenable to modern drug optimization techniques and to industrial scale-up. Vennerstrom would not describe the molecule precisely, because his US, Swiss and Australian research team are seeking a patent, but did tell the Bulletin it's a different type of peroxide [an oxygen-oxygen chemical bond] than the trioxane you find in the peroxide of Its molecular weight is in the range of 300-500: artemisinin's is 280. The peroxide is the active bit of But that's where the similarity with our molecules ends. Artemisinin and its. have a very elegant structure, but they can't be economically synthesized, and they also have some undesirable properties--they are very fast-acting but they have to be used in combinations with other drugs, because they are rapidly broken down in the body. That's where our molecule has major potential advantages. We're following up on it, and are looking at it as a prototype to make other derivatives said Vennerstrom. Next we have to identify the exact candidate for drug development ... it could be this exact molecule, or another; the activity of this one is outstanding but we want to get some better pharmacokinetic properties ... we'd like to increase the stability in the plasma ... and we're thinking about the optimal compound--one that's as cheap as possible to produce. And then we also have to consider the toxicity/therapeutic index. We've not seen any toxicity in this compound, but we haven't done all the experiments yet. This discovery was driven by a new synthetic reaction discovered by Karl Griesbaum of Karlsruhe University in Germany, said Vennerstrom. We realized that his technology could enable us to synthesize some very interesting compounds, and this particular peroxide is stable enough that we can do some very interesting chemistry on it. In that way quite similar to artemisinin. Also like artemisinin, the target of the drug is probably iron in the parasite, left over from the parasite's digestion of haemoglobin, Vennerstom believes. …