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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.

SUBMITTER: O'Neill PM

PROVIDER: S-EPMC5458052 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

O'Neill Paul M PM Amewu Richard K RK Charman Susan A SA Sabbani Sunil S Gnädig Nina F NF Straimer Judith J Fidock David A DA Shore Emma R ER Roberts Natalie L NL Wong Michael H-L MH Hong W David WD Pidathala Chandrakala C Riley Chris C Murphy Ben B Aljayyoussi Ghaith G Gamo Francisco Javier FJ Sanz Laura L Rodrigues Janneth J Cortes Carolina Gonzalez CG Herreros Esperanza E Angulo-Barturén Iñigo I Jiménez-Díaz María Belén MB Bazaga Santiago Ferrer SF Martínez-Martínez María Santos MS Campo Brice B Sharma Raman R Ryan Eileen E Shackleford David M DM Campbell Simon S Smith Dennis A DA Wirjanata Grennady G Noviyanti Rintis R Price Ric N RN Marfurt Jutta J Palmer Michael J MJ Copple Ian M IM Mercer Amy E AE Ruecker Andrea A Delves Michael J MJ Sinden Robert E RE Siegl Peter P Davies Jill J Rochford Rosemary R Kocken Clemens H M CHM Zeeman Anne-Marie AM Nixon Gemma L GL Biagini Giancarlo A GA Ward Stephen A SA

Nature communications 20170524

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 aga ...[more]

PMID: 28537265

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Project description:BACKGROUND:The problem of anti-malarial drug resistance is a long-term challenge faced by malaria control in Yunnan Province. Recently, the detection rates of chloroquine-resistant molecular markers (Plasmodium falciparum chloroquine resistant transporter, Pfcrt) and artemisinin-resistant molecular markers (P. falciparum kelch13 gene, ork13) were 85% and 35%, respectively. To understand the association of k13 gene mutation with artemisinin resistance in falciparum malaria cases, the difference in k13 gene differentiation between two populations and artemisinin resistance phenotype on falciparum malaria cases in Myanmar were analysed in this study. METHODS:This research involved all of falciparum malaria cases diagnosed continuously in Yunnan Province from 2013 to 2015 and some of falciparum malaria cases found in Lazar, Myanmar. Blood samples were taken from the former group for molecular epidemiological analysis of k13 gene mutations, and artemisinin resistance phenotypes of P. falciparum were observed in the latter group using the in vivo testing method recommended by the World Health Organization. Nested PCR was used to amplify the propeller domain of the k13 gene in P. falciparum, followed by sequencing. RESULTS:A total of 202 blood samples were collected from Yunnan Province and 382 blood samples were collected from falciparum malaria cases in Myanmar. 49 of 382 Myanmar cases were in vivo tested for artesunate resistance phenotype through full treatment course observation. At the same time, all the blood samples were screened for k13 gene mutation of P. falciparum. The genetic diversity of k13 was higher in the Plasmodium isolates from Yunnan Province than those from Myanmar cases. The genetic differentiation index of the two populations was 0.0410, where the intra- and inter-group variations were 95.9% and 4.1%, respectively. The odds ratio of artemisinin resistance phenotype and mutation at the locus 446 in k13 gene in Myanmar cases was 1.640, while the value was 1.840 based on the estimations of the mutations in the 12 loci. CONCLUSION:Although the Plasmodium isolates from Yunnan Province and those from Myanmar were collected from different sites, they still belong to the same geographical population. It is, therefore, reasonable to contrast the artemisinin resistance status of the Plasmodium population from Myanmar with the Plasmodium population from Yunnan Province. As a result, based on the molecular epidemiological investigation on k13 mutations of Plasmodium isolates in Yunnan Province and the determination of the artemisinin resistance on falciparum malaria cases in Myanmar, the positively genetic correlated was found between the k13 locus mutations with artemisinin resistance phenotype. This provides a basis for further monitoring the artemisinin resistance by detection some molecular markers in k13 gene of Plasmodium in Yunnan Province.

Dataset Information

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

Publications

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

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