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; Stephen A. Ward

doi:10.1038/ncomms15159

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 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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

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 language	English
Article number	15159
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15159
Publication status	Published - 24 May 2017

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O'Neill, P. M., Amewu, R. K., Charman, S. A., Sabbani, S., Gnädig, N. F., Straimer, J., Fidock, D. A., Shore, E. R., Roberts, N. L., Wong, M. H. L., Hong, W. D., Pidathala, C., Riley, C., Murphy, B., Aljayyoussi, G., Gamo, F. J., Sanz, L., Rodrigues, J., Cortes, C. G., ... Ward, S. A. (2017). A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nature Communications, 8, Article 15159. https://doi.org/10.1038/ncomms15159

@article{a5d525655868416194269b4c0c50a647,

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 I{\~n}igo Angulo-Bartur{\'e}n and Jim{\'e}nez-D{\'i}az, {Mar{\'i}a Bel{\'e}n} and Bazaga, {Santiago Ferrer} and Mart{\'i}nez-Mart{\'i}nez, {Mar{\'i}a Santos} and Brice Campo and Raman Sharma and Eileen Ryan and Shackleford, {David M.} and Simon Campbell and Smith, {Dennis A.} and Grennady Wirjanata and Rintis Noviyanti and Price, {Ric N.} and Jutta Marfurt and Palmer, {Michael J.} and Copple, {Ian M.} and Mercer, {Amy E.} and Andrea Ruecker and Delves, {Michael J.} and Sinden, {Robert E.} and Peter Siegl and Jill Davies and Rosemary Rochford and Kocken, {Clemens H.M.} and Zeeman, {Anne Marie} and Nixon, {Gemma L.} and Biagini, {Giancarlo A.} and Ward, {Stephen A.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = may,

day = "24",

doi = "10.1038/ncomms15159",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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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, 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, AM, Nixon, GL, Biagini, GA & Ward, SA 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

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 - Angulo-Barturén, Iñigo

AU - Jiménez-Díaz, María Belén

AU - Bazaga, Santiago Ferrer

AU - Martínez-Martínez, María Santos

AU - Campo, Brice

AU - Sharma, Raman

AU - Ryan, Eileen

AU - Shackleford, David M.

AU - Campbell, Simon

AU - Smith, Dennis A.

AU - Wirjanata, Grennady

AU - Noviyanti, Rintis

AU - Price, Ric N.

AU - Marfurt, Jutta

AU - Palmer, Michael J.

AU - Copple, Ian M.

AU - Mercer, Amy E.

AU - Ruecker, Andrea

AU - Delves, Michael J.

AU - Sinden, Robert E.

AU - Siegl, Peter

AU - Davies, Jill

AU - Rochford, Rosemary

AU - Kocken, Clemens H.M.

AU - Zeeman, Anne Marie

AU - Nixon, Gemma L.

AU - Biagini, Giancarlo A.

AU - Ward, Stephen A.

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.

UR - http://www.scopus.com/inward/record.url?scp=85019697683&partnerID=8YFLogxK

U2 - 10.1038/ncomms15159

DO - 10.1038/ncomms15159

M3 - Article

C2 - 28537265

AN - SCOPUS:85019697683

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 15159

ER -

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

Abstract

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