Identification and validation of edaravone remyelinating targets in oligodendrocyte progenitor cells

The main focus of regenerative therapies for Multiple Sclerosis (MS) is to induce the differentiation of oligodendrocyte progenitor cells (OPCs) present within areas of demyelination into remyelinating oligodendrocytes. We have recently performed a multiple phenotypic screening with the aim of repositioning drugs according to their myelin repair potential . This work has led to the identification and validation of edaravone as hit compound. Edaravone is a free radical scavenger, which has been approved as a neuroprotective agent for acute ischemic stroke in Japan and for amyotrophic lateral sclerosis in Japan and USA. In this multi-disciplinary project, we plan to identify the protein(s) through which edaravone elicits the remyelinating phenotype by a medicinal chemistry approach and to confirm both the drug-target engagement and the remyelinating activity of the identified target(s) in purified mouse OPC and lysolecithin demyelinated cerebellar slices. The tasks of the project are: 1. Design and synthesis of photoaffinity edaravone chemical derivatives through different synthetic strategies. 2. Evaluation of the biological activity and chemical-physical properties of edaravone derivatives. 3. Identification of edaravone targets and molecular interactions by mass spectrometry. 4. Validation of drug-target engagement in purified OPC by the cellular thermal shift assay (CETSA). 5. Validation of drug-target remyelinating activity testing known modulators of the identified target(s).