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COMPUTATIONALLY-GUIDED DRUG REPURPOSING ENABLES THE DISCOVERY OF KINASE TARGETS AND INHIBITORS AS NEW SCHISTOSOMICIDAL AGENTS
Quinase
Esquistossomicidas
Esquistossomose
Schistosoma mansoni
Resistencia a drogas
Humanos
Kinase
Schistosomicides
Schistosomiasis
Schistosoma mansoni
Drug Resistance
Humans
Autor
Afiliación
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, Brasil
London 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.
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, Brasil
London 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.
Resumen en ingles
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.
Palabras clave en portugues
DrogasQuinase
Esquistossomicidas
Esquistossomose
Schistosoma mansoni
Resistencia a drogas
Humanos
Palabras clave en ingles
DrugKinase
Schistosomicides
Schistosomiasis
Schistosoma mansoni
Drug Resistance
Humans
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