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Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents

Reker, Daniel and Seet, Michael and Pillong, Max and Koch, Christian P. and Schneider, Petra and Witschel, Matthias C. and Rottmann, Matthias and Freymond, Céline and Brun, Reto and Schweizer, Bernd and Illarionov, Boris and Bacher, Adelbert and Fischer, Markus and Diederich, François and Schneider, Gisbert. (2014) Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents. Angewandte Chemie, Jg. 53, Nr. 27. pp. 7079-7084.

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Official URL: http://edoc.unibas.ch/dok/A6348386

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Abstract

The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.
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:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Verlag Chemie
ISSN:0044-8249
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:12
Deposited On:10 Apr 2015 09:12

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