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Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites using Distinct Modes of Action

Schmitt, Esther and Schirle, Markus and Roggo, Silvio and Ostermann, Nils (2015) Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites using Distinct Modes of Action. ChemBioChem, 16 (17). pp. 2433-2436. ISSN 14394227

Abstract

Abstract: Malaria continues to be one of the major human diseases despite many efforts to limit its spread by prevention of infection or pharmaceutical treatment of patients. We have conducted a screen for anti-plasmodial compounds using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase PfAp3Aase, by affinity chromatography. Using a biochemical assay, we could show that Cyclomarin A is a specific inhibitor of the plasmodial enzyme but not the closest human homolog hFHIT. Co-crystallization experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme substrate complex. These results validate PfAp3Aase as a novel drug target for the treatment of malaria. We previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is the rare example of a natural product with two distinct and specific modes of action.

Item Type: Article
Date Deposited: 25 Apr 2016 23:45
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/25755

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