New001 Building research capacity for schistosomiasis drug discovery & development through high-content imaging & structural molecular biology studies

点击翻译按钮获取中文摘要

Helminth worm infections are a huge public health problem in countries with poverty and development issues where the economic impacts due to disease morbidity ultimately hamper their long-term sustainable growth. One of the main bottlenecks in the discovery of new anti-helminthic drugs is the lack of a fast, quantitative and reproductive assay method to screen and characterize the activity of candidate molecules in adult worm forms.The research activities to be carried out are briefly described below. New and improved research capacities will be built and disseminated in Brazil, maximising their impact on the issues of poverty and economic growth.1. The Hight Content Screen platforms (London and Rio) will identify novel small compounds active against adult schistosome worms based on a newly developed phenotypic screening strategy. The group in Rio de Janeiro is developing a novel platform for unbiased quantification of drug action against helminths that is based on automated imaging of unlabelled adult parasite worms and subsequent quantitative image analysis using custom-developed methods. A similar system based on the larval life stage of Schistosoma has been developed by the Bickle group at LSHTM (London, UK) and are able to lend technical expertise in both assay development and image analysis. Sharing ideas and experience with LSHTM would greatly accelerate the development and consolidation of the automated drug-screening platform for adult schistosomes.2. Dr. Furnham's group at LSHTM together with the FIOCRUZ group will develop a computational method to prioritize drug targets encoded within the genomes of Schistosoma species (in particular S. mansoni) genomes and to assess if drugs currently in clinical use can be repurposed to treat schistosomiasis. Deficiency in target data prevents further development of active compounds against schistosomiasis into drugs showing higher potency, better safety and reduced propensity to develop resistance. To circumvent this limitation, phenotypes induced by compounds with unknown mechanism will be compared to the ones produced by known drugs and a statistical model will then be used to classify the compounds according to known drug mechanisms. Concurrently, drugs with known molecular targets and already used in clinical use for other diseases will be computationally evaluated to assess their suitability to be repurposed to treat schistosomiasis.3. The Oxford Protein Production Facility has developed a range of highly specialized technologies incorporating robotic systems to enable the high throughput expression, purification and crystallization of recombinant proteins. This platform will be applied to the production of recombinant S. mansoni proteins with potential as drug targets either previously identified by our group at FIOCRUZ or selected from bioinformatics pipelines developed in [2] by Dr. Furnham's group at LSHTM.4. S. mansoni proteins that have been produced in [3] will be screened for crystallization using the high throughput automated pipeline in the OPPF-UK. Dr. Furnham's and Dr. Silva's groups will collaborate to solve the structures of the target proteins, and then employ structure-based design methods to optimize drug binding affinities.5. The best compounds will be selected for chemical derivatization and structural diversification to explore structure-activity relationships (SAR). Dr. Ferreira's group in UFRJ will synthesize the molecules. 6. Workshops in Brazil. Two workshops will be held at FIOCRUZ, one in each semester. The first workshop will have as its theme the high-throughput protein expression and crystallization. The second workshop will be on the Application of Computational Biology for Target Identification from Big Datasets.