Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents

dc.creatorGiuliani, Sandra
dc.creatorSilva, Arthur de Carvalho
dc.creatorBorba, Joyce Villa Verde Borba
dc.creatorRamos, Pablo Ivan Pereira
dc.creatorPaveley, Ross A
dc.creatorMuratov, Eugene N
dc.creatorAndrade, Carolina Horta
dc.creatorFurnham, Nicholas
dc.date2018-12-14T12:47:24Z
dc.date2018-12-14T12:47:24Z
dc.date2018
dc.date.accessioned2023-09-26T20:06:26Z
dc.date.available2023-09-26T20:06:26Z
dc.identifierGIULIANI, 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.identifier1553-734X
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/30592
dc.identifier10.1371/journal.pcbi.1006515
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8848620
dc.descriptionMedical 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).
dc.descriptionThe 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.
dc.formatapplication/pdf
dc.languageeng
dc.publisherPublic Library of Science
dc.rightsopen access
dc.subjectDrogas
dc.subjectQuinase
dc.subjectEsquistossomicidas
dc.subjectEsquistossomose
dc.subjectSchistosoma mansoni
dc.subjectResistencia a drogas
dc.subjectHumanos
dc.subjectDrug
dc.subjectKinase
dc.subjectSchistosomicides
dc.subjectSchistosomiasis
dc.subjectSchistosoma mansoni
dc.subjectDrug Resistance
dc.subjectHumans
dc.titleComputationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents
dc.typeArticle


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