Computationally-Guided Drug Repurposing Enables the Discovery of Kinase Targets and Inhibitors as New Schistosomicidal Agents

Mon9  Apr12:15pm(15 mins)
Where:
Stream 3 - Physics 0.15 Main

Authors

S Giuliani2; A C Silva4; J V Borba4; P I Ramos1; R A Paveley2; E N Muratov5; C H Andrade4N Furnham3
1 Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Brazil;  2 London School of Hygiene & Tropical Medicine, UK;  3 London School of Hygiene and Tropical Medicine, UK;  4 Universidade Federal de Goiás, Brazil;  5 University of North Carolina, United States

Discussion

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 three 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 a novel computational drug repurposing pipeline supported by high-content 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 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 as well as new inhibitors, and 22 newly identified targets. 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. 
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