Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10

Nat Commun. 2016 Jun 1;7:11647. doi: 10.1038/ncomms11647.

Abstract

RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ataxin-10 / antagonists & inhibitors*
  • Ataxin-10 / genetics
  • Ataxin-10 / metabolism
  • Base Pairing
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • DNA Repeat Expansion / genetics
  • Drug Design
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Microsatellite Repeats*
  • Mitochondria / drug effects
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / pharmacology
  • Primary Cell Culture
  • RNA Splicing / drug effects*
  • RNA, Messenger / antagonists & inhibitors*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacology
  • Spinocerebellar Ataxias / drug therapy
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / pathology
  • Structure-Activity Relationship

Substances

  • ATXN10 protein, human
  • Ataxin-10
  • Neuroprotective Agents
  • RNA, Messenger
  • Small Molecule Libraries
  • CASP3 protein, human
  • Caspase 3

Supplementary concepts

  • Spinocerebellar Ataxia 10