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

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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, Angulo-Barturén, Iñigo, Jiménez-Díaz, María Belén, Bazaga, Santiago Ferrer, Martínez-Martínez, María Santos, Campo, Brice, Sharma, Raman, Ryan, Eileen, Shackleford, David M, Campbell, Simon, Smith, Dennis A, Wirjanata, Grennady, Noviyanti, Rintis, Price, Ric N, Marfurt, Jutta, Palmer, Michael J, Copple, Ian M, Mercer, Amy E, Ruecker, Andrea, Delves, Michael J, Sinden, Robert E, Siegl, Peter, Davies, Jill, Rochford, Rosemary, Kocken, Clemens H M, Zeeman, Anne-Marie, Nixon, Gemma L, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (2017) 'A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.'. Nature Communications, Vol 8, e15159.

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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.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 38 Drug action.
QX Parasitology > QX 20 Research (General)
QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1038/ncomms15159
SWORD Depositor: JISC Pubrouter
Depositing User: JISC Pubrouter
Date Deposited: 08 Jun 2017 09:50
Last Modified: 06 Feb 2018 13:14
URI: http://archive.lstmed.ac.uk/id/eprint/7196

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