Development of Non-Hydrolyzable Inositol Pyrophosphate Analogs and Their Application in the Identification of Inositol Pyrophosphate Binding Partners.

• Applicant: Dr. Anastasia Hager
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253400140

To ensure its own survival a cell needs to react as flexibly as possible to external influences. These external stimuli are transducted within the cell by a complex action of cell organelles, proteins and signaling molecules eventually influencing intracellular metabolism and gene expression. Thus, cells are capable of withstanding chemical stress, reacting to changes of extracellular hormone concentrations and to evolve an immune response. A dysfunction of such signaling pathways can lead to diverse medical conditions. Thus, an understanding of the signaling pathways and their misfunctions can serve for development of new therapeutics. Small signaling molecules are the main actors in the signal transduction pathways. Among them, phosphorylated inositols are an important group of intracellular messengers in eukaryotic cells. Although pyrophosphorylated inositol derivatives (IPPs) have been known for more than 20 years and found to be involved in essential cellular processes, the understanding of their mechanism of action and the characterization of their protein binding partners is still limited. The understanding of this IPP code would define the IPP regulatory role in cell physiology and manifest therapeutic potential for diseases linked to the misregulation of the IPP signaling pathway, such as insulin resistance, type II diabetes and certain types of cancer. Therefore, this proposal focuses on the development of new chemical tools for the identification of IPP specific protein binding partners. Non-hydrolyzable analogs of several IPPs will be prepared and their biological features compared to those of the parent compounds. Based on these results, the non-hydrolyzable analogs will be employed for affinity capture, and, in parallel, for covalent capture of the IPP interacting proteins. Ultimately, the comprehensive analysis of the IPP protein targets is expected to highlight specific domains, and thus the IPP code, unveiling the regulatory role of IPP messengers. Consequently, these chemical tools would provide us with a better understanding of diseases caused by the dysfunction of the IPP pathway which can ultimately be exploited for the development of novel therapeutics.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Dorothea Fiedler