TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides

Bioorg Chem. 2019 Mar:84:254-259. doi: 10.1016/j.bioorg.2018.11.042. Epub 2018 Nov 27.

Abstract

TAR DNA binding protein 43 (TDP-43) is a key target in amyotrophic lateral sclerosis (ALS) treatment. Here, based on hydrophobic tagging strategy, we designed and synthesized a series of single or double hydrophobic tags conjugated peptides D1-D8. Among them, it was found that D4 displayed strongest ability to induce TDP-43 degradation in cells. D4 could reduce TDP-43 induced cytotoxicity. Besides, D4 could reduce TDP-43 levels in a transgenic drosophila model.

Keywords: Hydrophobic tagging; Protein degradation; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Drosophila melanogaster / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology

Substances

  • DNA-Binding Proteins
  • Peptides
  • TARDBP protein, human