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

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

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    Abstract

    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.

    Original languageEnglish
    Article number15159
    Pages (from-to)1-12
    Number of pages12
    JournalNature Communications
    Volume8
    DOIs
    Publication statusPublished - 24 May 2017

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