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

07 Feb 2011

Susan A. Charman, Sarah Arbe-Barnes, Ian C. Bathurst, Reto Brun, Michael Campbell, William N. Charman, Francis C. K. Chiu, Jacques Chollet, J. Carl Craft, Darren J. Creek, Yuxiang Dong, Hugues Matile, Melanie Maurer, Julia Morizzi, Tien Nguyen, Petros Papastogiannidis, Christian Scheurer, David M. Shackleford, Kamaraj Sriraghavan, Lukas Stingelin, Yuanqing Tang, Heinrich Urwyler, Xiaofang Wang, Karen L. White, Sergio Wittlin, Lin Zhou, and Jonathan L. Vennerstrom

Proceedings of the National Academy of Sciences of the United States of America

DOI: 10.1073/pnas.1015762108

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 IC50 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.

View the article on the PNAS website.