Novartis unveils new class of preclinical antimalarial

Novartis and its collaborators have unveiled a new class of promising antimalarials – the spiroindolones. The lead candidate in the class, NITD609, yielded promising efficacy and safety data in in vitro and in vivo preclinical models, the company reported in Science on 3 September.

The spiroindolones, and NITD609 specifically, were identified by screening around 12,000 compounds directly against whole-cell intraerythrocytic Plasmodium parasites. Further analysis revealed that compound kills blood stages of the parasite, is active against drug-resistant parasites and has pharmacokinetic properties that are compatible with once-daily dosing. The drug also appears to be safe; no adverse events or histopathological findings were noted in rats given high doses of drug.

Cheryl Cole of Girls Aloud made the headlines recently for contracting the mosquito-borne illness in Tanzania in June while on holiday
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The authors point to several lines of data to show that NITD609 has a different mode of action to the artemisinin derivatives, a standard treatment for malaria. They show, for instance, that unlike mefloquine and artemisinin, NITD609 rapidly suppresses malarial protein synthesis. They also show that development of resistance to NITD609 is mediated by mutations in the ATPase PfATP4, but that these drug-resistant mutants are still susceptible to other classes of reference antimalarial.

As yet, the researchers have not determined the drug's mechanism of action; they speculate, however, that one possibility is that it targets PfATP4.

Novartis says that preclinical evaluation of NITD609 is ongoing.

Return of the "whole microorganism" screen

Dr Timothy Wells – CSO of the Medicines for Malaria Venture based in Switzerland, who was not involved in the study – writes an accompanying commentary in Science that this study shows that "whole microorganism screening" is once again bearing fruit in drug discovery efforts.

For the past decade, he explains, many groups and companies have focused on molecular-based screens, in which scientists test whether compounds inhibit or activate key enzymes or receptors. Problematically, he continues, often the targets that are being used in the screens cannot be validated until the candidates actually make it into the clinic.

Of late, however, there has been a return to whole microorganism screening, whereby drug discoverers search for compounds that affect cells and microorganisms without any understanding or consideration for the mechanism of action. Such an approach not only seems to have a higher hit rate than molecular screening, he writes, but may have the potential to shave "several years" off the drug development process.

Indeed, he continues, NITD609 "was optimized into a preclinical candidate in just 3 years. That is a turbocharged pace."

"Do these developments mean that the days of searching for molecular targets for antiparasitic drugs are over? Far from it. Target-based approaches are extremely useful once you know the target, and cell-based screening is one way of finding new molecular targets."