Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4281-7. doi: 10.1073/pnas.1512289112. Epub 2015 Jul 20.

Abstract

Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production. BRD5631 can serve as a valuable tool for studying the role of autophagy in the context of cellular homeostasis and disease.

Keywords: Crohn’s disease; autophagy; high-throughput screening; small-molecule probes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects*
  • Bacteria / drug effects
  • Carrier Proteins / metabolism
  • Cell Aggregation / drug effects
  • Genetics, Medical*
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism
  • Models, Biological
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Niemann-Pick Disease, Type C / genetics*
  • Niemann-Pick Disease, Type C / metabolism
  • Niemann-Pick Disease, Type C / pathology*
  • Peptides / metabolism
  • Phenotype
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Carrier Proteins
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Peptides
  • Small Molecule Libraries
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • polyglutamine