5 years ago

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
Nina F. Gnädig, W. David Hong, Judith Straimer, Dennis A. Smith, Gemma L. Nixon, Amy E. Mercer, David M. Shackleford, Jill Davies, Rosemary Rochford, Natalie L. Roberts, Laura Sanz, Paul M. O’Neill, Michael H.-L. Wong, Raman Sharma, Ben Murphy, Anne-Marie Zeeman, María Belén Jiménez-Díaz, David A. Fidock, Janneth Rodrigues, Grennady Wirjanata, Eileen Ryan, Clemens H. M. Kocken, Carolina Gonzalez Cortes, Ian M. Copple, Santiago Ferrer Bazaga, Peter Siegl, Chris Riley, Ric N. Price, Brice Campo, Jutta Marfurt, Stephen A. Ward, Sunil Sabbani, Francisco Javier Gamo, Michael J. Delves, Chandrakala Pidathala, Andrea Ruecker, Richard K. Amewu, Susan A. Charman, Rintis Noviyanti, Simon Campbell, Ghaith Aljayyoussi, Iñigo Angulo-Barturén, Esperanza Herreros, Giancarlo A. Biagini, Emma R. Shore, Michael J. Palmer, María Santos Martínez-Martínez, Robert E. Sinden
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.

Publisher URL: http://www.nature.com/articles/ncomms15159

DOI: 10.1038/ncomms15159

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