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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

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Author(s):
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Batista, Fernando A. [1] ; Bosch, Soraya S. [2] ; Butzloff, Sabine [3] ; Lunev, Sergey [1] ; Meissner, Kamila A. [2] ; Linzke, Marleen [2] ; Romero, Atilio R. [1] ; Wang, Chao [1] ; Mueller, Ingrid B. [3] ; Domling, Alexander S. S. [1] ; Groves, Matthew R. [1] ; Wrenger, Carsten [2]
Total Authors: 12
Affiliation:
[1] Univ Groningen, Dept Pharm, Struct Biol Unit, XB20 Drug Design, Groningen - Netherlands
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, Sao Paulo - Brazil
[3] Bernhard Nocht Inst Trop Med, Hamburg - Germany
Total Affiliations: 3
Document type: Journal article
Source: MICROBIOLOGYOPEN; v. 8, n. 7 JUL 2019.
Web of Science Citations: 1
Abstract

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. (AU)

FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
Grantee:Carsten Wrenger
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/24790-9 - Dissecting Plasmodium falciparum EXP1/GST2 for xenobiotic defence in glucose-6-phosphate dehydrogenase deficiency
Grantee:Kamila Anna Meissner
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/17577-9 - Analysis of the ATCase catalysis within the amino acid metabolism of the human malaria parasite Plasmodium falciparum
Grantee:Soraya Soledad Bosch
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 17/03966-4 - Targeting lipoic acid salvage and biosynthesis pathways in MRSA
Grantee:Carsten Wrenger
Support type: Regular Research Grants
FAPESP's process: 14/23330-9 - Morphologic Analysis of the Apicoplast Formation in Plasmodium falciparum
Grantee:Marleen Linzke
Support type: Scholarships in Brazil - Doctorate