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Decoy peptides that inhibit TNF signaling by disrupting the TNF homotrimeric oligomer

Nasir Javaid1,2, Bilal Ahmad1,2, Mahesh Chandra Patra1

  • 1Department of Molecular Science and Technology, Ajou University, Suwon, Korea.

The FEBS Journal
|July 14, 2024
PubMed

Insights

New decoy peptides (TIDs) effectively inhibit tumor necrosis factor (TNF) signaling by disrupting its functional trimer formation. TID3c demonstrates promising potential for developing novel peptide-based anti-TNF therapeutics for inflammatory diseases.

Area of Science:

  • Biochemistry
  • Immunology
  • Drug Discovery

Background:

  • Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that activates apoptotic, necroptotic, and inflammatory pathways.
  • Dysregulated TNF signaling contributes to various inflammatory diseases, identifying TNF as a key therapeutic target.

Purpose of the Study:

  • To develop novel peptide-based inhibitors targeting TNF signaling.
  • To investigate the mechanism of action for TNF-inhibiting decoys (TIDs).

Main Methods:

  • Selection of 12-mer peptides from the TNF-TNFR interface based on binding energies.
  • In vitro assays to assess inhibition of TNF-mediated cytokine secretion and cell death.
  • Cell-based assays to evaluate downstream signaling.
  • In silico modeling and simulations to analyze peptide-TNF interactions.

Main Results:

  • Selected decoy peptides (TIDs) inhibited TNF signaling by disrupting TNF homotrimer formation.
  • TID3c exhibited enhanced efficacy in disrupting TNF trimerization and induced high molecular weight TNF oligomers.
  • In silico studies confirmed stable complex formation between TIDs and TNF via hydrogen bonds and electrostatic interactions.

Conclusions:

  • TIDs represent a promising strategy for inhibiting TNF signaling.
  • TID3c shows potential as a lead compound for developing peptide-based anti-TNF therapeutics.
  • Disruption of TNF trimerization is a viable mechanism for anti-TNF therapy.
Keywords:
TNFantagonistsdecoy peptideoligomertherapeutics

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