Direct targeting of TDP-43, from small molecules to biologics: The therapeutic landscape

Liberty Francois-Moutal, David Donald Scott, May Khanna

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations


Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1158-1166
Number of pages9
JournalRSC Chemical Biology
Issue number4
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Biochemistry


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