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Licensed Unlicensed Requires Authentication Published by De Gruyter April 18, 2014

Selective modulation of plasmodial Hsp70s by small molecules with antimalarial activity

Ingrid L. Cockburn, Aileen Boshoff, Eva-Rachele Pesce and Gregory L. Blatch
From the journal Biological Chemistry

Abstract

Plasmodial heat shock protein 70 (Hsp70) chaperones represent a promising new class of antimalarial drug targets because of the important roles they play in the survival and pathogenesis of the malaria parasite Plasmodium falciparum. This study assessed a set of small molecules (lapachol, bromo-β-lapachona and malonganenones A, B and C) as potential modulators of two biologically important plasmodial Hsp70s, the parasite-resident PfHsp70-1 and the exported PfHsp70-x. Compounds of interest were assessed for modulatory effects on the steady-state basal and heat shock protein 40 (Hsp40)-stimulated ATPase activities of PfHsp70-1, PfHsp70-x and human Hsp70, as well as on the protein aggregation suppression activity of PfHsp70-x. The antimalarial marine alkaloid malonganenone A was of particular interest, as it was found to have limited cytotoxicity to mammalian cell lines and exhibited the desired properties of an effective plasmodial Hsp70 modulator. This compound was found to inhibit plasmodial and not human Hsp70 ATPase activity (Hsp40-stimulated), and hindered the aggregation suppression activity of PfHsp70-x. Furthermore, malonganenone A was shown to disrupt the interaction between PfHsp70-x and Hsp40. This is the first report to show that PfHsp70-x has chaperone activity, is stimulated by Hsp40 and can be specifically modulated by small molecule compounds.


Corresponding author: Gregory L. Blatch, Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa; and College of Health and Biomedicine, Victoria University, Melbourne 8001, Victoria, Australia, e-mail:

Acknowledgments

Many thanks to Prof. M.T. Davies Coleman and Dr. R. Keyzers for supplying the compounds included in this study, and thanks to Dr. J. de la Mare and Dr. E. Prinsloo for assistance with mammalian cell culture and SPR experiments, respectively. This research was funded by a Deutsche Forschungsgemeinschaft (DFG) German-African Cooperation Project in Infectology grant [DFG (Ref: LI 402/12-0)] as well as by the National Research Foundation (NRF, South Africa). ILC was funded by Rhodes University and the NRF.

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Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2014-0138) offers supplementary material, available to authorized users.


Received: 2014-2-15
Accepted: 2014-4-12
Published Online: 2014-4-18
Published in Print: 2014-11-1

©2014 by De Gruyter

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