Drug discovery for new mitophagy regulators

The main objective of this project is to identify new Parkin-dependent and Parkin-independent modulators of mitophagy. Our approach will use reverse chemical genetics with a phenotypic screen for mitophagy index in collaboration with the group of Patricia Boya that has developed a new method to assess mitophagy. Ankar Pharma will provide in house library of small molecules (MW less than 500 daltons) composed of cell permeable heterocycles that have been previously synthetized in different programs searching for neuroprotective compounds.

The PhD student will test them in a phenotypic assay using stable SHSY-5Y cells expressing MitoEGFPmCherry reporter construct. Using candidate drugs and molecular regulators selected, the PhD student will also evaluate the impact of mitophagy modulation in models of neurodegeneration. In particular, he/she will assess how selected compounds that induce mitophagy are able to prevent retinal degeneration associated with retinal ganglion cell damage and age-related glaucoma models in collaboration with Patricia Boya group or how these compounds may restore protein homeostasis, such TDP-43, in different ALS and FTD cell-based models. Moreover the ESR will conduct a medicinal chemistry programme to improve the drug-like properties of the hit compounds to be tested in the above animal models and perform chemical modifications that (without losing biological activity) increase solubility for in-tissue delivery. Drugs will be properly formulated in food, water, eye drops, intravitreal or intraperitoneal administration, and the animals will be purchased from Jackson Mice. The more promising compounds will also be tested in disease models within DRIVE.