title: Self-assembling small molecules form nanofibrils that bind procaspase-3 to promote activation.
abstract: Modulating enzyme function with small-molecule activators, as opposed to inhibitors, offers new opportunities for drug discovery and allosteric regulation. We previously identified a compound, called 1541, from a high-throughput screen (HTS) that stimulates activation of a proenzyme, procaspase-3, to generate mature caspase-3. Here we further investigate the mechanism of activation and report the surprising finding that 1541 self-assembles into nanofibrils exceeding 1 μm in length. These particles are an unanticipated outcome from an HTS that have properties distinct from standard globular protein aggregators. Moreover, 1541 nanofibrils function as a unique biocatalytic material that activates procaspase-3 via induced proximity. These studies demonstrate a novel approach for proenzyme activation through binding to fibrils, which may mimic how procaspases are naturally processed on protein scaffolds.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
authors: Julie A
authors: JA
authors: Zorn
authors: Holger
authors: H
authors: Wille
authors: Dennis W
authors: DW
authors: Wolan
authors: James A
authors: JA
authors: Wells
mesh_terms: D053148:Caspase 3 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects*; D004792:Enzyme Precursors / Q000378:metabolism*; D057139:Nanofibers / Q000737:chemistry* / Q000648:ultrastructure; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004792:Enzyme Precursors; D054852:Small Molecule Libraries; D053148:Caspase 3