Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins.

ABSTRACT: The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. 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 degradat

SUBMITTER: Jones CL 

PROVIDER: S-EPMC5720355 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature