Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
Texto Completo: | https://www.arca.fiocruz.br/handle/icict/30592 |
Resumo: | Medical Research Council (MRC; https://mrc.ukri.org) Research Methodology Fellowship (MRC: MR/K020420). CHA thanks Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; http://www.cnpq.br), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; http://www.capes.gov.br) and Goias Research Support Foundation (FAPEG; Fapeg.go. gov.br) for financial support and fellowships. ACS and JVVBB are supported by CAPES fellowships. ENM appreciates support from National Institutes of Health (NIH; https://www.nih.gov) (grant 1U01CA207160) and CNPq (grant 400760/2014- 2). CHA is CNPq research fellow and supported by “L’Ore´al-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” (https://www.forwomeninscience.com/en/home). |
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Giuliani, SandraSilva, Arthur de CarvalhoBorba, Joyce Villa Verde BorbaRamos, Pablo Ivan PereiraPaveley, Ross AMuratov, Eugene NAndrade, Carolina HortaFurnham, Nicholas2018-12-14T12:47:24Z2018-12-14T12:47:24Z2018GIULIANI, S. et al. Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents. PLoS Computational Biology, v. 14, n. 10, p. e1006515, 2018.1553-734Xhttps://www.arca.fiocruz.br/handle/icict/3059210.1371/journal.pcbi.1006515Medical Research Council (MRC; https://mrc.ukri.org) Research Methodology Fellowship (MRC: MR/K020420). CHA thanks Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; http://www.cnpq.br), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; http://www.capes.gov.br) and Goias Research Support Foundation (FAPEG; Fapeg.go. gov.br) for financial support and fellowships. ACS and JVVBB are supported by CAPES fellowships. ENM appreciates support from National Institutes of Health (NIH; https://www.nih.gov) (grant 1U01CA207160) and CNPq (grant 400760/2014- 2). CHA is CNPq research fellow and supported by “L’Ore´al-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” (https://www.forwomeninscience.com/en/home).London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology. London, United Kingdom.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, Goiás, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, Goiás, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, BrasilLondon School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology. London, United Kingdom.University of North Carolina. Division of Chemical Biology and Medicinal Chemistry. Laboratory for Molecular Modeling. Chapel Hill, NC, United States of America / Odessa National Polytechnic University. Department of Chemical Technology. Odessa, Ukraine.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratory for Molecular Modeling and Drug Design. Goiânia, Goiás, Brasil / University of Campinas. Institute of Biology. Department of Genetics, Evolution, Microbiology and Immunology, Laboratory of Tropical Diseasesampinas. São Paulo, SP, Brazil.London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology. London, United Kingdom.The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite's biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease.engPublic Library of ScienceDrogasQuinaseEsquistossomicidasEsquistossomoseSchistosoma mansoniResistencia a drogasHumanosDrugKinaseSchistosomicidesSchistosomiasisSchistosoma mansoniDrug ResistanceHumansComputationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agentsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/30592/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALGiuliani S. Computationally-guided...2018.pdfGiuliani S. Computationally-guided...2018.pdfapplication/pdf2779949https://www.arca.fiocruz.br/bitstream/icict/30592/2/Giuliani%20S.%20Computationally-guided...2018.pdf0e6b6d4ec4071eea8cd3a8e929484bb7MD52TEXTGiuliani S. Computationally-guided...2018.pdf.txtGiuliani S. 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dc.title.pt_BR.fl_str_mv |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
title |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
spellingShingle |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents Giuliani, Sandra Drogas Quinase Esquistossomicidas Esquistossomose Schistosoma mansoni Resistencia a drogas Humanos Drug Kinase Schistosomicides Schistosomiasis Schistosoma mansoni Drug Resistance Humans |
title_short |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
title_full |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
title_fullStr |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
title_full_unstemmed |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
title_sort |
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents |
author |
Giuliani, Sandra |
author_facet |
Giuliani, Sandra Silva, Arthur de Carvalho Borba, Joyce Villa Verde Borba Ramos, Pablo Ivan Pereira Paveley, Ross A Muratov, Eugene N Andrade, Carolina Horta Furnham, Nicholas |
author_role |
author |
author2 |
Silva, Arthur de Carvalho Borba, Joyce Villa Verde Borba Ramos, Pablo Ivan Pereira Paveley, Ross A Muratov, Eugene N Andrade, Carolina Horta Furnham, Nicholas |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Giuliani, Sandra Silva, Arthur de Carvalho Borba, Joyce Villa Verde Borba Ramos, Pablo Ivan Pereira Paveley, Ross A Muratov, Eugene N Andrade, Carolina Horta Furnham, Nicholas |
dc.subject.other.pt_BR.fl_str_mv |
Drogas Quinase Esquistossomicidas Esquistossomose Schistosoma mansoni Resistencia a drogas Humanos |
topic |
Drogas Quinase Esquistossomicidas Esquistossomose Schistosoma mansoni Resistencia a drogas Humanos Drug Kinase Schistosomicides Schistosomiasis Schistosoma mansoni Drug Resistance Humans |
dc.subject.en.pt_BR.fl_str_mv |
Drug Kinase Schistosomicides Schistosomiasis Schistosoma mansoni Drug Resistance Humans |
description |
Medical Research Council (MRC; https://mrc.ukri.org) Research Methodology Fellowship (MRC: MR/K020420). CHA thanks Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; http://www.cnpq.br), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; http://www.capes.gov.br) and Goias Research Support Foundation (FAPEG; Fapeg.go. gov.br) for financial support and fellowships. ACS and JVVBB are supported by CAPES fellowships. ENM appreciates support from National Institutes of Health (NIH; https://www.nih.gov) (grant 1U01CA207160) and CNPq (grant 400760/2014- 2). CHA is CNPq research fellow and supported by “L’Ore´al-UNESCO-ABC Para Mulheres na Ciência” and “L’Oréal-UNESCO International Rising Talents” (https://www.forwomeninscience.com/en/home). |
publishDate |
2018 |
dc.date.accessioned.fl_str_mv |
2018-12-14T12:47:24Z |
dc.date.available.fl_str_mv |
2018-12-14T12:47:24Z |
dc.date.issued.fl_str_mv |
2018 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
GIULIANI, S. et al. Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents. PLoS Computational Biology, v. 14, n. 10, p. e1006515, 2018. |
dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/30592 |
dc.identifier.issn.pt_BR.fl_str_mv |
1553-734X |
dc.identifier.doi.none.fl_str_mv |
10.1371/journal.pcbi.1006515 |
identifier_str_mv |
GIULIANI, S. et al. Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents. PLoS Computational Biology, v. 14, n. 10, p. e1006515, 2018. 1553-734X 10.1371/journal.pcbi.1006515 |
url |
https://www.arca.fiocruz.br/handle/icict/30592 |
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eng |
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Public Library of Science |
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Public Library of Science |
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