Article
Computationally-guided drug repurposing enables the discovery of kinase targets and inhibitors as new schistosomicidal agents
Registro en:
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
Autor
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
Resumen
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). 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.