An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties

ACS Chem Biol. 2020 Nov 20;15(11):2854-2859. doi: 10.1021/acschembio.0c00494. Epub 2020 Oct 12.


In this study, we targeted the N-terminal domain (NTD) of transactive response (TAR) DNA binding protein (TDP-43), which is implicated in several neurodegenerative diseases. In silico docking of 50K compounds to the NTD domain of TDP-43 identified a small molecule (nTRD22) that is bound to the N-terminal domain. Interestingly, nTRD22 caused allosteric modulation of the RNA binding domain (RRM) of TDP-43, resulting in decreased binding to RNA in vitro. Moreover, incubation of primary motor neurons with nTRD22 induced a reduction of TDP-43 protein levels, similar to TDP-43 RNA binding-deficient mutants and supporting a disruption of TDP-43 binding to RNA. Finally, nTRD22 mitigated motor impairment in a Drosophila model of amyotrophic lateral sclerosis. Our findings provide an exciting way of allosteric modulation of the RNA-binding region of TDP-43 through the N-terminal domain.

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects*
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Binding Sites / drug effects
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Drosophila
  • Humans
  • Molecular Docking Simulation
  • Protein Domains / drug effects*
  • RNA / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • DNA-Binding Proteins
  • Small Molecule Libraries
  • TARDBP protein, human
  • RNA