ProFIDs: Probes to Fold the Intrinsically Disordered

ProFIDs: Probes to Fold the Intrinsically Disordered ProFIDs: Probes to Fold the Intrinsically Disordered In this collaborative project, the Heyden group will work in collaboration with Dr. Alice Soragni at the medical school of the University of Los Angeles to develop small molecules, such as peptides, which are able to specifically bind to intrinsically disordered proteins (IDPs), to affect their conformational equilibrium, and to promote the formation of collapsed protein states. Two key applications are envisioned: 1) The IDP fused in sarcoma (FUS) is known to phase-separate into liquid droplets inside living cells to form so-called membrane-less organelles. The latter is specifically amplified in the presence of point mutations that are linked to amyotropic lateral sclerosis (ALS), but the physiological consequences of this observation are not fully understood. The development of small molecular probes, which induce partial folding of FUS and prevent the formation of liquid droplets would provide a unique analytical tool to investigate the detailed role that the liquid-liquid phase separation of FUS plays in pathological contexts and in healthy cells. 2) We will use the design strategies envisioned in this project for the development of small molecules with a specific binding affinity to intrinsically disordered proteins, to create specific ligands for highly challenging drug targets such as the MYC protein. The MYC protein, an oncoprotein that is tightly linked to numerous forms of cancer, has been previously been described as undruggable due to the lack of a well-defined native structure, which severely impedes traditional drug development techniques. The development of theoretical (Heyden lab at ASU) and experimental approaches (Soragni lab at UCLA) to design specific small molecules that are able to bind to the intrinsically disordered regions of MYC allow for a coupling to existing systems, which tag proteins for degradation in the cell (PROTAC: proteolysis targeting chimeras).