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Purification of functional Plasmodium falciparum tubulin allows for the identification of parasite-specific microtubule inhibitors

William Graham Hirst, Dominik Fachet, Benno Kuropka, Christoph Weise, View ORCID ProfileKevin Saliba, View ORCID ProfileSimone Reber
doi: https://doi.org/10.1101/2021.05.25.445550
William Graham Hirst
1IRI Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
2Research School of Biology, The Australian National University, Canberra, ACT, Australia
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Dominik Fachet
1IRI Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
2Research School of Biology, The Australian National University, Canberra, ACT, Australia
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Benno Kuropka
3Freie Universität Berlin, Institute of Chemistry and Biochemistry, Core Facility BioSupraMol, Berlin, Germany
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Christoph Weise
3Freie Universität Berlin, Institute of Chemistry and Biochemistry, Core Facility BioSupraMol, Berlin, Germany
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Kevin Saliba
2Research School of Biology, The Australian National University, Canberra, ACT, Australia
4Medical School, The Australian National University, Canberra, ACT, Australia
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Simone Reber
1IRI Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
5University of Applied Sciences Berlin, Berlin, Germany
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  • ORCID record for Simone Reber
  • For correspondence: simone.reber@iri-lifesciences.de
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ABSTRACT

Cytoskeletal proteins are essential for parasite proliferation, growth, and transmission, and therefore represent promising drug targets. While αβ-tubulin, the molecular building block of microtubules, is an established drug target in a variety of cancers, we still lack substantial knowledge of the biochemistry of parasite tubulins, which would allow us to exploit the structural divergence between parasite and human tubulins. Indeed, mechanistic insights have been limited by the lack of purified, functional parasite tubulin. In this study, we isolated Plasmodium falciparum tubulin that is assembly-competent and shows specific microtubule dynamics in vitro. We further present mechanistic evidence that two compounds selectively interact with parasite over host microtubules and inhibit Plasmodium microtubule polymerization at substoichiometric compound concentrations. The ability of compounds to selectively disrupt protozoan microtubule growth without affecting human microtubules provides the exciting possibility for the targeted development of novel antimalarials.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 25, 2021.
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Purification of functional Plasmodium falciparum tubulin allows for the identification of parasite-specific microtubule inhibitors
William Graham Hirst, Dominik Fachet, Benno Kuropka, Christoph Weise, Kevin Saliba, Simone Reber
bioRxiv 2021.05.25.445550; doi: https://doi.org/10.1101/2021.05.25.445550
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Purification of functional Plasmodium falciparum tubulin allows for the identification of parasite-specific microtubule inhibitors
William Graham Hirst, Dominik Fachet, Benno Kuropka, Christoph Weise, Kevin Saliba, Simone Reber
bioRxiv 2021.05.25.445550; doi: https://doi.org/10.1101/2021.05.25.445550

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