Computational chemogenomics drug repositioning strategy enables the discovery of epirubicin as a new repurposed hit for Plasmodium falciparum and P. vivax
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2020
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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 re duce costs, risks, and time-to-market. Herein, we have used this strategy to iden tify 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 iden tify 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 ob served for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsuffi-
ciency 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 epiru bicin 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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DNA gyrase, Chemogenomics, Drug repositioning, Epirubicin, Malaria
Citação
FERREIRA,Letícia Tiburcio et al. Computational chemogenomics drug repositioning strategy enables the discovery of epirubicin as a new repurposed hit for Plasmodium falciparum and P. vivax. Antimicrobial Agents and Chemotherapy, Washington, v. 64, n. 9, e02041-19, 2020. DOI: 10.1128/AAC.02041-19. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449180/. Acesso em: 9 set. 2024.