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

摘要

Author summary The rise of resistance through the intensive use of drugs targeted to treat specific infectious diseases means that new therapeutics are continually required. Diseases common in the tropics and sub-tropics, classified as neglected tropical diseases, suffer from a lack of new drug treatments due to the difficulty in developing new drugs and the lack of market incentive. One such disease is schistosomiasis, a major human helminth disease caused by worms from the genus Schistosoma. It is currently treated by a 40-year old drug, praziquantel, but its widespread use has led to signs of drug-resistance emerging, with no alternative effective treatments available. To meet this challenge, we have developed an innovative computational drug repurposing pipeline supported by experimental phenotypic screening. Protein kinases emerged from our pipeline as interesting new biological targets. Given that many human kinase inhibitors have been successfully applied specially in cancer therapy and kinases have conserved structures and functions, we also undertook a detailed analysis of the kinases present in all infective Schistosoma species and human host. This allowed identification of new Schistosoma-specific kinase targets and suggest approved drugs to be used for treating schistosomiasis as well as opening new avenues to treat this neglected disease.