期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 64, 期 9, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02041-19
关键词
DNA gyrase; chemogenomics; drug repositioning; epirubicin; malaria
资金
- CNPq
- FAPESP
- FAPEG
- FCT
- L'Oreal-UNESCO-ABC Para Mulheres na Ciencia
- L'Oreal-UNESCO International Rising Talents
- FCT of Portugal
- FAPESP of Brazil [PTDC/SAU-PAR/28459/2017]
- Ministry of Science of Brazil
- MCTI/CNPq [14/2013]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
- Instituto Serrapilheira [2013/13119-6, G-1709-16618]
- INOVA Fiocruz
- FAPESP [2017/02031-1, 2015/20774-6, 2018/24878-9, 2017/01986-8, 2015/03553-6]
- Brazilian CNPq/FAPEG [300508/2017-4]
- Vetenskapsradet (Swedish Research Council) [2016-05627]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-PAR/28459/2017] Funding Source: FCT
- Swedish Research Council [2016-05627] Funding Source: Swedish Research Council
Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.
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