PT  - JOURNAL ARTICLE
AU  - William Graham Hirst
AU  - Dominik Fachet
AU  - Benno Kuropka
AU  - Christoph Weise
AU  - Kevin Saliba
AU  - Simone Reber
TI  - Purification of functional <em>Plasmodium falciparum</em> tubulin allows for the identification of parasite-specific microtubule inhibitors
AID  - 10.1101/2021.05.25.445550
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.25.445550
4099  - http://biorxiv.org/content/early/2021/05/25/2021.05.25.445550.short
4100  - http://biorxiv.org/content/early/2021/05/25/2021.05.25.445550.full
AB  - 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 StatementThe authors have declared no competing interest.