A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.
O'Neill PM., Amewu RK., Charman SA., Sabbani S., Gnädig NF., Straimer J., Fidock DA., Shore ER., Roberts NL., Wong MH-L., Hong WD., Pidathala C., Riley C., Murphy B., Aljayyoussi G., Gamo FJ., Sanz L., Rodrigues J., Cortes CG., Herreros E., Angulo-Barturén I., Jiménez-Díaz MB., Bazaga SF., Martínez-Martínez MS., Campo B., Sharma R., Ryan E., Shackleford DM., Campbell S., Smith DA., Wirjanata G., Noviyanti R., Price RN., Marfurt J., Palmer MJ., Copple IM., Mercer AE., Ruecker A., Delves MJ., Sinden RE., Siegl P., Davies J., Rochford R., Kocken CHM., Zeeman A-M., Nixon GL., Biagini GA., Ward SA.
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.