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

by Sandra Giuliani, Arthur C. Silva, Joyce V. V. B. Borba, Pablo I. P. Ramos, Ross A. Paveley, Eugene N. Muratov, Carolina Horta Andrade, Nicholas Furnham 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 t he 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 genusSchistosoma 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 ofSchistosoma japonicum, as well as updated kinomes ofS.mansoni andS.haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets ...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research