Light-activatable peptidomimetic inhibitors for CRAC channel

Calcium ion is the most widely used intracellular messenger in eukaryotic cells and controls many different biological processes. The primary calcium entry route via plasma membranes in non-excitable cells involves calcium-release activated calcium (CRAC) channels. The CRAC channel complex is composed of two molecular key components: the highly calcium selective plasma membrane channel Orai1 and the calcium sensor protein stromal interaction molecule 1 (STIM1), which is embedded in the endoplasmic reticulum. This protein complex interacts in respond to calcium depletion of the endoplasmic reticulum. Abnormal CRAC channel activity has been associated with a number of human disorders including immunodeficiency, autoimmunity and acute pancreatitis. In this project, we aim to identify new peptidomimetic scaffolds with inhibitory properties for future therapeutic interventions targeting the CRAC channel complex. The proposed work will utilize a tightly coordinated interdisciplinary approach, which combines computational methods with advanced organic and peptide synthesis as well as experimental biophysical techniques. The identification of STIM1 and Orai1 proteins as key components of CRAC channels provides an opportunity to screen for and design drugs that can modulate channel activity and help to better understand and manipulate calcium signaling pathways. Up to present, only few CRAC channel inhibitors have reached human clinical trials. Our international research team includes experts in the fields of CRAC channel pharmacology and biophysics (Division of Biophysics, Medical University of Graz, Prof. Rainer Schindl and Dr. Bernadett Bacsa), computer-aided drug design (Division of Physiological Chemistry, Medical University of Graz, Ass.Prof. Pedro Alejandro Snchez Murcia), synthetic organic methods (Institute of Chemistry, University Graz, Assoc. Prof. Toma Glasnov) together with peptide and peptidomimetic synthesis (Research Center for Natural Sciences, Budapest, Dr. Istvn Mandity Mndity, Dr. Kata Horvti and Dr. Viktor Farkas). In a close collaboration, our goal is to provide valuable light-responsive peptidomimetic tools that should allow precise spatial and temporal inhibition over the CRAC channel function. This will further allow us to study the underlying pharmacological mechanisms (photopharmacology) and the involved structure-activity relationships of the generated molecules. Based on the results, we will be able to fine-tune these into a second generation more effective molecular probes, or, in the best case, even into potential drug candidates.