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The effect of helix-inducing constraints and downsizing upon a transcription block survival-derived functional cJun

Andrew Brennan1, James T Leech1, Neil M Kad2

  • 1Department of Life Sciences, University of Bath, Bath BA2 7AY, UK.

Cell Reports. Physical Science
|October 24, 2022
PubMed

Insights

Researchers developed a novel screening platform to identify peptide inhibitors of cJun, a key cancer target. They optimized a peptide antagonist, creating a smaller, more stable, and potent inhibitor for therapeutic development.

Area of Science:

  • Molecular Biology
  • Drug Discovery
  • Cancer Therapeutics

Background:

  • Inhibition of cJun is a promising strategy for cancer therapy.
  • The transcription block survival (TBS) platform screens for peptide antagonists of transcription factors.

Purpose of the Study:

  • To develop functional peptide antagonists of cJun DNA binding using the TBS platform.
  • To derive a minimal active peptide sequence with enhanced stability and potency.

Main Methods:

  • Screening a large peptide library (>131,000 members) using the TBS platform.
  • Iterative truncation and side-chain cyclization to optimize peptide sequence.
  • Characterization of binding affinity (K_D) and functional antagonism (IC50).

Main Results:

  • A 63-mer peptide antagonist of cJun-TRE DNA binding was identified.
  • A smaller, dual lactamized peptide retained low nM affinity (K_D = 0.2 nM) and functional antagonism (IC50 = 13 µM).
  • The optimized peptide demonstrated increased stability in human serum compared to its non-lactamized form.

Conclusions:

  • The TBS platform effectively identifies functional peptide antagonists.
  • Optimized peptide antagonists of cJun show potential for cancer therapy due to enhanced potency and stability.
  • Specific residues in the acidic region are crucial for functional antagonism.
Keywords:
activator protein-1cJunfunctional antagonistspeptide antagonistpeptide cyclizationprotein-protein interactionstranscription block survivaltranscription factor

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