Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

• Published in: MicrobiologyOpen (Weinheim) 2019-07, Vol.8 (7), p.e00779-n/a
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Cloning; Drug resistance; drug target validation; E coli; Enzymes; Experiments; Hypotheses; Interference; Localization; Malaria; Metabolism; Metabolites; Mutagenesis; oligomeric state; Original; Parasites; phenotypic mapping; Plasmodium falciparum; Proteins; structural biology; Vector-borne diseases
• ISSN: 2045-8827; 2045-8827
• DOI: 10.1002/mbo3.779

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. Challenges in drug target validation can possibly be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support this hypothesis by demonstrating that recombinant expression of mutant proteins within Plasmodium 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.