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September 1, 2015
An international team of scientists has developed a compound that looks promising as a novel antimalarial agent. The compound targets dihydroorotate dehydrogenase (DHODH), an enzyme involved in thePlasmodium parasite’s de novo production of pyrimidines required for nucleic acid synthesis (Phillips MA et al. Sci Transl Med. 2015;7:296ra111).
Tracy Hampton, PhD
DSM265, named after several of the collaborators’ cities (Dallas, Seattle, and Melbourne), was the 265th version of an initial compound targeting DHODH, and is highly selective toward the Plasmodium falciparum—but not the human—form of the enzyme.
In multiple experimental models—including human cells, rodents, dogs, and monkeys—the drug appeared safe and effective at inhibiting parasitemia. DSM265 was also active against various strains of P falciparumin vitro, including those that were multidrug-resistant.
Unlike most malaria drugs that only act on the parasite during its blood stage of the life cycle, DSM265 arrests growth of P falciparum at both the blood and liver stages of infection. Furthermore, while other drugs often require daily dosing, pharmacokinetic models suggest that a single oral dose of DSM265 could be effective for treating infection or, if dosed once-weekly, as chemoprevention.