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, Laura Sanz, Janneth Rodrigues, Carolina Gonzalez Cortes, Esperanza Herreros, Iñigo 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 and Stephen A. Ward
Additional contact information
Paul M. O’Neill: University of Liverpool
Richard K. Amewu: University of Liverpool
Susan A. Charman: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University
Sunil Sabbani: University of Liverpool
Nina F. Gnädig: Columbia University College of Physicians and Surgeons
Judith Straimer: Columbia University College of Physicians and Surgeons
David A. Fidock: Columbia University College of Physicians and Surgeons
Emma R. Shore: University of Liverpool
Natalie L. Roberts: University of Liverpool
Michael H.-L. Wong: University of Liverpool
W. David Hong: University of Liverpool
Chandrakala Pidathala: University of Liverpool
Chris Riley: University of Liverpool
Ben Murphy: University of Liverpool
Ghaith Aljayyoussi: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine
Francisco Javier Gamo: Tres Cantos Medicines Development Campus
Laura Sanz: Tres Cantos Medicines Development Campus
Janneth Rodrigues: Tres Cantos Medicines Development Campus
Carolina Gonzalez Cortes: Tres Cantos Medicines Development Campus
Esperanza Herreros: Tres Cantos Medicines Development Campus
Iñigo Angulo-Barturén: Tres Cantos Medicines Development Campus
María Belén Jiménez-Díaz: Tres Cantos Medicines Development Campus
Santiago Ferrer Bazaga: Tres Cantos Medicines Development Campus
María Santos Martínez-Martínez: Tres Cantos Medicines Development Campus
Brice Campo: Medicines for Malaria Venture, ICC
Raman Sharma: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine
Eileen Ryan: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University
David M. Shackleford: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University
Simon Campbell: Medicines for Malaria Venture, ICC
Dennis A. Smith: Medicines for Malaria Venture, ICC
Grennady Wirjanata: Menzies School of Health Research, Charles Darwin University
Rintis Noviyanti: Eijkman Institute for Molecular Biology
Ric N. Price: Menzies School of Health Research, Charles Darwin University
Jutta Marfurt: Menzies School of Health Research, Charles Darwin University
Michael J. Palmer: Medicines for Malaria Venture, ICC
Ian M. Copple: School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool
Amy E. Mercer: School of Biomedical Sciences, MRC Centre for Drug Safety Science, University of Liverpool
Andrea Ruecker: Imperial College London
Michael J. Delves: Imperial College London
Robert E. Sinden: Imperial College London
Peter Siegl: Medicines for Malaria Venture, ICC
Jill Davies: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine
Rosemary Rochford: University of Colorado
Clemens H. M. Kocken: Biomedical Primate Research Centre
Anne-Marie Zeeman: Biomedical Primate Research Centre
Gemma L. Nixon: University of Liverpool
Giancarlo A. Biagini: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine
Stephen A. Ward: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15159

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