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 & 2 others Eileen Ryan, David M Shackleford

Research output: Contribution to journalArticleResearchpeer-review

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
Number of pages10
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 24 May 2017

Cite this

O'Neill, Paul M. ; Amewu, Richard K. ; Charman, Susan A ; Sabbani, Sunil ; Gnädig, Nina F. ; Straimer, Judith ; Fidock, David A ; Shore, Emma R. ; Roberts, Natalie L. ; Wong, Michael H.L. ; Hong, W. David ; Pidathala, Chandrakala ; Riley, Chris ; Murphy, Ben ; Aljayyoussi, Ghaith ; Gamo, Francisco Javier ; Sanz, Laura ; Rodrigues, Janneth ; Cortes, Carolina Gonzalez ; Herreros, Esperanza ; Ryan, Eileen ; Shackleford, David M. / A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. In: Nature Communications. 2017 ; Vol. 8.
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title = "A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance",
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.",
author = "O'Neill, {Paul M.} and Amewu, {Richard K.} and Charman, {Susan A} and Sunil Sabbani and Gn{\"a}dig, {Nina F.} and Judith Straimer and Fidock, {David A} and Shore, {Emma R.} and Roberts, {Natalie L.} and Wong, {Michael H.L.} and Hong, {W. David} and Chandrakala Pidathala and Chris Riley and Ben Murphy and Ghaith Aljayyoussi and Gamo, {Francisco Javier} and Laura Sanz and Janneth Rodrigues and Cortes, {Carolina Gonzalez} and Esperanza Herreros and Eileen Ryan and Shackleford, {David M}",
year = "2017",
month = "5",
day = "24",
doi = "10.1038/ncomms15159",
language = "English",
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O'Neill, PM, Amewu, RK, Charman, SA, Sabbani, S, Gnädig, NF, Straimer, J, Fidock, DA, Shore, ER, Roberts, NL, Wong, MHL, Hong, WD, Pidathala, C, Riley, C, Murphy, B, Aljayyoussi, G, Gamo, FJ, Sanz, L, Rodrigues, J, Cortes, CG, Herreros, E, Ryan, E & Shackleford, DM 2017, 'A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance', Nature Communications, vol. 8, 15159. https://doi.org/10.1038/ncomms15159

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. / O'Neill, Paul M.; Amewu, Richard K.; Charman, Susan A; Sabbani, Sunil; Gnädig, Nina F.; Straimer, Judith; Fidock, David A; Shore, Emma R.; Roberts, Natalie L.; Wong, Michael H.L.; Hong, W. David; Pidathala, Chandrakala; Riley, Chris; Murphy, Ben; Aljayyoussi, Ghaith; Gamo, Francisco Javier; Sanz, Laura; Rodrigues, Janneth; Cortes, Carolina Gonzalez; Herreros, Esperanza; Ryan, Eileen; Shackleford, David M.

In: Nature Communications, Vol. 8, 15159, 24.05.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance

AU - O'Neill, Paul M.

AU - Amewu, Richard K.

AU - Charman, Susan A

AU - Sabbani, Sunil

AU - Gnädig, Nina F.

AU - Straimer, Judith

AU - Fidock, David A

AU - Shore, Emma R.

AU - Roberts, Natalie L.

AU - Wong, Michael H.L.

AU - Hong, W. David

AU - Pidathala, Chandrakala

AU - Riley, Chris

AU - Murphy, Ben

AU - Aljayyoussi, Ghaith

AU - Gamo, Francisco Javier

AU - Sanz, Laura

AU - Rodrigues, Janneth

AU - Cortes, Carolina Gonzalez

AU - Herreros, Esperanza

AU - Ryan, Eileen

AU - Shackleford, David M

PY - 2017/5/24

Y1 - 2017/5/24

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms15159

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