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Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum
Author(s) -
Batista Fernando A.,
Bosch Soraya S.,
Butzloff Sabine,
Lunev Sergey,
Meissner Kamila A.,
Linzke Marleen,
Romero Atilio R.,
Wang Chao,
Müller Ingrid B.,
Dömling Alexander S. S.,
Groves Matthew R.,
Wrenger Carsten
Publication year - 2019
Publication title -
microbiologyopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.881
H-Index - 36
ISSN - 2045-8827
DOI - 10.1002/mbo3.779
Subject(s) - druggability , plasmodium falciparum , drug discovery , in vivo , biology , computational biology , function (biology) , mutant , drug , microbiology and biotechnology , malaria , biochemistry , genetics , pharmacology , gene , immunology
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.

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