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A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Phillips, Margaret A. and Lotharius, Julie and Marsh, Kennan and White, John and Dayan, Anthony and White, Karen L. and Njoroge, Jacqueline W. and El Mazouni, Farah and Lao, Yanbin and Kokkonda, Sreekanth and Tomchick, Diana R. and Deng, Xiaoyi and Laird, Trevor and Bhatia, Sangeeta N. and March, Sandra and Ng, Caroline L. and Fidock, David A. and Wittlin, Sergio and Lafuente-Monasterio, Maria and Benito, Francisco Javier Gamo and Alonso, Laura Maria Sanz and Martinez, Maria Santos and Jimenez-Diaz, Maria Belen and Bazaga, Santiago Ferrer and Angulo-Barturen, Iñigo and Haselden, John N. and Louttit, James and Cui, Yi and Sridhar, Arun and Zeeman, Anna-Marie and Kocken, Clemens and Sauerwein, Robert and Dechering, Koen and Avery, Vicky M. and Duffy, Sandra and Delves, Michael and Sinden, Robert and Ruecker, Andrea and Wickham, Kristina S. and Rochford, Rosemary and Gahagen, Janet and Iyer, Lalitha and Riccio, Ed and Mirsalis, Jon and Bathhurst, Ian and Rueckle, Thomas and Ding, Xavier and Campo, Brice and Leroy, Didier and Rogers, M. John and Rathod, Pradipsinh K. and Burrows, Jeremy N. and Charman, Susan A.. (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science translational medicine, Vol. 7, H. 296 , 296ra111.

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Official URL: http://edoc.unibas.ch/dok/A6411218

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Abstract

Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Sep 2015 14:30
Deposited On:04 Sep 2015 14:30

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