A library-derived peptide inhibitor of the BZLF1 transcription factor

Research output: Contribution to journalArticlepeer-review

Abstract

Transcription factor dysregulation is associated with many diseases, including cancer. Peptide-based molecules are increasingly recognised as important modulators of difficult intracellular protein–protein interaction targets, with peptide library screening consequently proven to be a viable strategy in developing inhibitors against a wide range of transcription factors (TFs). However, current strategies simply select the highest affinity of binding to a target TF rather than the ability to inhibit TF function. Here, we utilise our Transcription Block Survival (TBS) screening platform to enable high-throughput identification of peptides that inhibit TFs from binding to cognate DNA sites, hence inhibiting functionality. In this study, we explore whether the TBS can be expanded to derive a potent and functional peptide inhibitor of the BZLF1 transcription factor. The library-derived peptide, AcidicW, is shown to form a more stable dimer with BZLF1 than the BZLF1 homodimer, with a thermal denaturation temperature exceeding 80°C. AcidicW can also functionally inhibit the BZLF1:TRE DNA interaction with high potency and an IC50 of 612 nM.

Original languageEnglish
Article numbere3557
Number of pages12
JournalJournal of Peptide Science
Early online date2 Dec 2023
DOIs
Publication statusPublished - 2 Dec 2023

Bibliographical note

Funding: Biotechnology and Biological Sciences Research Council - BB/R017956/1; Cancer Research UK - A26941; Medical Research Council - MR/T028254/1

Funding

J.M.M. is grateful to Cancer Research U.K. (A26941), the Medical Research Council (MR/T028254/1) and the Biotechnology and Biological Sciences Research Council (BB/R017956/1). S.K.M. acknowledges a Pump Priming Grant from the Department of Life Sciences, University of Bath.

FundersFunder number
Department of Life Sciences
Medical Research CouncilMR/T028254/1
Biotechnology and Biological Sciences Research CouncilBB/R017956/1
Cancer Research UKA26941
University of Bath

Keywords

  • BZLF1
  • PCA
  • ZEBRA
  • peptide antagonists
  • peptide screening
  • transcription factor

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Structural Biology
  • Biochemistry
  • Pharmacology
  • Organic Chemistry

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