A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3178807
Author(s) Phillips, Margaret A.; Lotharius, Julie; Marsh, Kennan; White, John; Dayan, Anthony; White, Karen L.; Njoroge, Jacqueline W.; El Mazouni, Farah; Lao, Yanbin; Kokkonda, Sreekanth; Tomchick, Diana R.; Deng, Xiaoyi; Laird, Trevor; Bhatia, Sangeeta N.; March, Sandra; Ng, Caroline L.; Fidock, David A.; Wittlin, Sergio; Lafuente-Monasterio, Maria; Gamo Benito, Francisco Javier; Sanz Alonso, Laura Maria; Santos Martinez, Maria; Belen Jimenez-Diaz, Maria; Ferrer Bazaga, Santiago; Angulo-Barturen, Inigo; Haselden, John N.; Louttit, James; Cui, Yi; Sridhar, Arun; Zeeman, Anna-Marie; Kocken, Clemens; Sauerwein, Robert; Dechering, Koen; Avery, Vicky M.; Duffy, Sandra; Delves, Michael; Sinden, Robert; Ruecker, Andrea; Wickham, Kristina S.; Rochford, Rosemary; Gahagen, Janet; Iyer, Lalitha; Riccio, Ed; Mirsalis, Jon; Bathhurst, Ian; Rueckle, Thomas; Ding, Xavier; Campo, Brice; Leroy, Didier; Rogers, M. John; Rathod, Pradipsinh K.; Burrows, Jeremy N.; Charman, Susan A.
Author(s) at UniBasel Wittlin, Sergio
Year 2015
Title A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria
Journal Science translational medicine
Volume 7
Number 296
Pages / Article-Number 296ra111
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.

Publisher American Association for the Advancement of Science
ISSN/ISBN 1946-6234
edoc-URL http://edoc.unibas.ch/dok/A6411218
Full Text on edoc No
Digital Object Identifier DOI 10.1126/scitranslmed.aaa6645
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/26180101
ISI-Number WOS:000358738400004
Document type (ISI) Article
 
   

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07/08/2020