Chemical Tools to Probe the Role of Bromodomains in the Parasite Schistosoma mansoni

• Applicant: Professor Dr. Matthias Schiedel
• Subject Area: Pharmacy
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323850458

Lysine acetylation has emerged as a key post-translational protein modification found in various proteins throughout the cellular environment and across the range of species. Acetyl-lysine modifications create binding sites for bromodomains, which are modules of epigenetic reader proteins mediating protein-protein interactions with target proteins, which include histones but also non-histone proteins. The recent discovery of the 3D-structure of many bromodomains as well as the development of highly potent and selective ligands for the bromodomain classes BET (bromodomain and extra C-terminal domain) and CREBBP (CREB binding protein) has stimulated intensive research activity in diverse therapeutic areas. In oncology, BET proteins were identified as key regulators of the expression of oncogenes as well as anti-apoptotic proteins. Thus, a number of BET bromodomain ligands are in clinical trials for the treatment of cancers, but also other diseases like type 2 diabetes, viral infection, and atherosclerosis. Despite the rapid progress in the validation of human bromodomains as therapeutic targets, the function of these protein modules in other species is poorly understood.This proposal seeks support for research to create a toolkit of synthetic chemical probes to investigate the role of bromodomains in the life cycle of parasites, specifically Schistosoma mansoni. The blood fluke S. mansoni is the main pathogen of schistosomiasis (bilharzia), a life-threatening disease that affects 210 million people worldwide, and up to 200 000 people die from it each year. Praziquantel is currently the only way of treating schistosomiasis. Although an effective drug, praziquantel has a number of known side effects and due to its mass administration first parasites resistant to praziquantel have been identified. Therefore, the search for new therapeutic concepts to treat schistosomiasis has a high priority for the management and treatment of this neglected disease. Considering the limitations of current treatments of this disease, we wish to investigate novel mechanisms for developing tool compounds and, ultimately, drugs to treat schistosomiasis. In view of the fundamental functions of bromodomains in regulating transcription in human cells, we hypothesise that bromodomain-containing proteins will play equally important roles in other organisms. 18 putative bromodomain-containing proteins have been predicted in S. mansoni, and we have identified proteins that show significant identity to certain human bromodomains. Consequently, these proteins might prove to be novel therapeutic targets to impede the function of S. mansoni and open new avenues for the treatment of schistosomiasis. In doing this work we will begin to understand whether epigenetic targets in parasites, like S. mansoni, parallel the relevance of the related machinery in humans and thus whether they are potential drug targets for treating parasite-based diseases more widely.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Stuart J. Conway, Ph.D.