2. Academic Validation
  3. An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties

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.
Niloufar Mollasalehi 1 2 3,  Liberty Francois-Moutal 1 2,  David D Scott 1 2,  Judith A Tello 1 2,  Haley Williams 1 2,  Brendan Mahoney 4,  Jacob M Carlson 1 2,  Yue Dong 5 6,  Xingli Li 7,  Victor G Miranda 1 2,  Vijay Gokhale 8,  Wei Wang 5 6,  Sami J Barmada 7,  May Khanna 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
  • 2 Center of Innovation in Brain Science, Tucson, Arizona 85721, United States.
  • 3 Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721-0041, United States.
  • 4 Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, California 90095, United States.
  • 5 Arizona Center for Drug Discovery, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 6 Pharmacology and Toxicology Department, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 7 Department of Neurology, University of Michigan Health System, Ann Arbor, Michigan 48109, United States.
  • 8 Bio5 Institute, University of Arizona, Tucson, Arizona 85721, United States.
PMID: 33044808 DOI: 10.1021/acschembio.0c00494
Abstract

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.

Figures
Products