Computational chemogenomics drug repositioning strategy enables the discovery of epirubicin as a new repurposed hit for Plasmodium falciparum and P. vivax

Letícia Tiburcio Ferreira, Juliana Rodrigues, Gustavo Capatti Cassiano, Tatyana Almeida Tavella, Kaira Cristina Peralis Tomaz, Djane Clarys Baia-Da-Silva, Macejane Ferreira Souza, Marilia Nunes do Nascimento Lima, Melina Mottin, Ludimila Dias Almeida, Juliana Calit, Maria Carolina Silva de Barros Puça, Gisely Cardoso Melo, Daniel Youssef Bargieri, Stefanie Costa Pinto Lopes, Marcus Vinicius Guimarães Lacerda, Elizabeth Bilsland, Per Sunnerhagen, Bruno J. Neves, Carolina Horta AndradePedro Vitor Lemos Cravo, Fabio Trindade Maranhão Costa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere02041-19
Pages (from-to)e02041-e02058
Number of pages17
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number9
DOIs
Publication statusPublished - Sep 2020

Keywords

  • Chemogenomics
  • DNA gyrase
  • Drug repositioning
  • Epirubicin
  • Malaria

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