Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Charman, S. A. and Arbe-Barnes S., and Bathurst, I. C. and Brun, R. and Campbell, M. and Charman, W. N. and Chiu, F. C. and Chollet, J. and Craft, J. C. and Creek, D. J. and Dong, Y. and Matile, H. and Maurer, M. and Morizzi, J. and Nguyen, T. and Papastogiannidis, P. and Scheurer, C. and Shackleford, D. M. and Sriraghavan, K. and Stingelin, L. and Tang, Y. and Urwyler, H. and Wang, X. and White, K. L. and Wittlin, S. and Zhou, L. and Vennerstrom, J. L.. (2011) Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, H. 11. pp. 4400-4405.

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Official URL: http://edoc.unibas.ch/dok/A6002363

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Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:11 Oct 2012 15:32
Deposited On:11 Oct 2012 15:30

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