Selective inhibition of Schistosoma mansoni guanidino kinase as potential new therapeutic target for the treatment of bilharzia – SmGKinhibit

The project SmGKnhibit is aimed to the conception of novel and selective inhibitors of a specific ATP-dependent guanidino kinase of Schistosoma sp. (SmGK) a mammal parasite causing bilharzia diseases. - - The inhibitors will be designed to be selective against the parasite, by studying comparatively the host and parasite homologous enzymes and by exploiting specific differences identified in the enzymes. Detailed action mode of the prepared inhibitors, both at the molecular level as well as at the physiological level, will be provided in order to validate during the project SmGK as a potential new pharmacological target. - - We will take advantage of the newly developed fragment-based design methodology that we have recently developed in Lyon, France. The partners in Lyon have already collaborated for the validation of the chemical design methodology with thea report of novel and original inhibitor of mammal muscle creatine kinase (CK), the mammal homologue of SmCK [Bretonnet et al., J. Med. Chem. 2007 in the press). We have demonstrated that the methodology lead to high-value, novel hit molecules presenting original scaffold, simple enough to be easily developed by medicinal chemistry into more active and selective compounds. - - Our consortium includes an existing and validated in-house chemical library of molecular fragments suitable for initial affinity screening, a dedicated very high filed NMR system (600 MHz NMR and manipulating robots), high-performance molecular computation (in silico screening and interaction modelling), multi-step synthesis of designed potent inhibitors, evaluation of the enzymatic activity in vitro (partners 1, 2 CNRS - Université Lyon), then on cultured parasites and possibly on infected animals (partner 3, INSERM Pasteur INSERM Lille). - - All necessary prerequisite elements, as the parasite enzyme large-scale (10mg-scale) production as well as the structural biology basis are already available. The 3 partners are all leaders in their field of competences and own unic know-how and materials and dedicated instruments in France waranted the successness of the proposed project ...