Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

Autor(es):Mostrar menos -

Ferreira, Leticia Tiburcio ^[1] ; Rodrigues, Juliana ^[2] ; Cassiano, Gustavo Capatti ^{[1, 3]} ; Tavella, Tatyana Almeida ^[1] ; Peralis Tomaz, Kaira Cristina ^[1] ; Baia-da-Silva, Djane Clarys ^[4] ; Souza, Macejane Ferreira ^{[5, 4]} ; do Nascimento Lima, Marilia Nunes ^[2] ; Mottin, Melina ^[2] ; Almeida, Ludimila Dias ^[6] ; Calit, Juliana ^[7] ; Silva de Barros Puca, Maria Carolina ^[4] ; Melo, Gisely Cardoso ^[5] ; Bargieri, Daniel Youssef ^[7] ; Pinto Lopes, Stefanie Costa ^{[5, 4]} ; Guimaraes Lacerda, Marcus Vinicius ^[5] ; Bilsland, Elizabeth ^[6] ; Sunnerhagen, Per ^[8] ; Neves, Bruno Junior ^{[2, 9]} ; Andrade, Carolina Horta ^{[1, 2]} ; Lemos Cravo, Pedro Vitor ^{[3, 9]} ; Maranhao Costa, Fabio Trindade ^[1]

Afiliação do(s) autor(es)

^[1] Univ Campinas UNICAMP, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, Campinas, SP - Brazil

^[2] Univ Fed Goias, Fac Farm, LabMol, Lab Mol Modeling & Drug Design, Goiania, Go - Brazil

^[3] Univ Nova Lisboa, Inst Higiene & Med Trop, Global Hlth & Trop Med GHTM, Lisbon - Portugal

^[4] Fundacao Oswaldo Cruz FIOCRUZ, Inst Leonidas & Maria Deane, Manaus, Amazonas - Brazil

^[5] Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas - Brazil

^[6] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, Synthet Biol Lab, Campinas, SP - Brazil

^[7] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

^[8] Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg - Sweden

^[9] Ctr Univ Anapolis UniEVANGEL, LabChem Lab Cheminformat, Anapolis, Go - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 64, n. 9 SEP 2020.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 17/02031-1 - Avaliação do potencial antimalárico da Epirrubicina (4'-epidoxorrubicina)
• Beneficiário: Letícia Tiburcio Ferreira
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/24878-9 - Pesquisa de compostos bloqueadores da transmissão de Plasmodium usando novos modelos experimentais
• Beneficiário: Juliana Calit Paim
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/13119-6 - Biologia celular e genética molecular de hemoparasitas
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/03553-6 - Engenharia genética de leveduras para a descoberta de novos medicamentos
• Beneficiário: Elizabeth Bilsland
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/01986-8 - Determinação da especificidade ao substrato de transportadores da membrana plasmática de Saccharomyces cerevisiae e de Homo sapiens
• Beneficiário: Ludimila Dias Almeida
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/20774-6 - Identificação de inibidores de quinases com atividade antimalárica baseado em análises de quimiogenômica, bioinformática e fenotípicas: enfoque em Plasmodium vivax.
• Beneficiário: Gustavo Capatti Cassiano
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado