Small molecule enhancement of 20S proteasome activity targets intrinsically disordered proteins.

The 20S proteasome is the main protease for degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceed proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disor-ders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered protein, alpha-synuclein but not structured proteins. These small molecules enhancers of 20S proteasome can serve as leads to explore the therapeutic potential of 20S activation, or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation.