Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax
| Autor: | Bruno J. Neves, Gisely Cardoso de Melo, Fabio T. M. Costa, Kaira C. P. Tomaz, Marilia N. N. Lima, Carolina Horta Andrade, Stefanie C. P. Lopes, Macejane Ferreira Souza, Per Sunnerhagen, Gustavo Capatti Cassiano, Letícia Tiburcio Ferreira, Juliana Rodrigues, Maria Carolina Silva de Barros Puça, Juliana Calit, Tatyana Almeida Tavella, Melina Mottin, Daniel Y. Bargieri, Ludimila Dias Almeida, Djane Clarys Baia-da-Silva, Marcus V. G. Lacerda, Elizabeth Bilsland, Pedro Cravo |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
0303 health sciences Drug discovery 030231 tropical medicine Plasmodium vivax Plasmodium falciparum Computational biology Biology biology.organism_classification DNA gyrase 03 medical and health sciences Drug repositioning chemistry.chemical_compound 0302 clinical medicine Infectious Diseases chemistry parasitic diseases Chemogenomics medicine Pharmacology (medical) Plasmodium yoelii 030304 developmental biology Epirubicin medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 64 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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