Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

Fernando A. Batista, Soraya S Bosch, Sabine Butzloff, Sergey Lunev, Kamila A Meissner, Marleen Linzke, Atilio R Romero, Chao Wang, Ingrid B Müller, Alexander S S Dömling, Matthew R Groves, Carsten Wrenger

OnderzoeksoutputAcademicpeer review

1 Citaat (Scopus)
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Samenvatting

The appearance of multi-drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross-reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging-particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials.

Originele taal-2English
Artikelnummere779
Aantal pagina's14
TijdschriftMicrobiologyOpen
Volume8
Nummer van het tijdschrift7
Vroegere onlinedatum28-feb-2019
DOI's
StatusPublished - jul-2019

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