Last year, AstraZeneca, the global drug company, closed its research centre in Bengaluru. One of the legacies of the work carried out there is the identification of a novel candidate drug for malaria. In laboratory tests, this molecule has shown that it was fast acting and remained in the blood for an
extended period of time, creating the possibility of a single-dose treatment, according to a paper published recently.
The project received the backing of the Switzerland-based nonprofit foundation, Medicines for Malaria Venture. It also drew on the expertise of scientists with another drug giant, GlaxoSmithKline, as well as researchers at Columbia and Harvard universities in the U.S.
The first step in a research effort that lasted about three and a half years was to screen a library of half a million compounds that AstraZeneca possessed. An automated process rapidly tested these molecules, looking for ones that could kill the malaria parasite, Plasmodium falciparum, at the stage in its complex lifecycle when it infects red blood cells. P. falciparum is responsible for causing the most dangerous forms of disease.
The most promising compound to emerge from this quest, however, had poor solubility and also affected a molecule involved in maintaining the heart’s rhythmic beating, according to a paper about the work that was published this week in Nature Communications.
Utilising chemistry and pharmacological knowledge, this initial hit compound’s structure was modified to reduce its limitations and enhance desirable properties, remarked Vasan K. Sambandamurthy, who was one of the senior scientists at AstraZeneca’s Bengaluru centre involved in the project and is a corresponding author of the paper.
In an iterative process, some 1,000 compounds were then synthesised in order to identify lead molecules with the requisite levels of potency, specificity as well as other necessary characteristics. One of the molecules — ‘compound 12’ — came out on top.
Compound 12 showed that it could rapidly kill blood stages of P. falciparum when it was administered to mice infected by the parasite. “Faster reduction in the blood parasite burden is essential to provide quick relief from clinical symptoms and to minimise the risk of emergence of drug resistance,” the scientists observed in the paper.
Based on levels of the molecule in the blood of mice, rats and dogs given compound 12, scientists computed that in humans “a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days.” When given in combination with another drug, “compound 12 is predicted to cure patients following a single-dose treatment.”
The drug appeared to target a protein secreted by the parasite after it infected a red blood cell and which was essential for its growth and development inside the cell. Other antimalarial drugs do not target this protein.
Moreover, when P. falciparum was exposed to the increasing concentrations of the drug, mutations that made the parasite resistant to its action arose only very infrequently.
Tests were also carried out with a panel of over 1,900 P. falciparum parasites isolated from patients globally as well as laboratory strains displaying varying forms of resistance to antimalarial agents currently in use and under development. None of the parasites proved resistant to compound 12.
Toxicity studies in rats and tests in guinea pigs for cardiovascular effects showed that this candidate drug has good safety margins, the paper noted. Medicines for Malaria Venture was evaluating compound 12 with further preclinical safety studies, said Dr. Sambandamurthy.
