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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 language | English |
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Article number | e3557 |
Number of pages | 12 |
Journal | Journal of Peptide Science |
Early online date | 2 Dec 2023 |
DOIs | |
Publication status | Published - 2 Dec 2023 |
Bibliographical note
Funding: Biotechnology and Biological Sciences Research Council - BB/R017956/1; Cancer Research UK - A26941; Medical Research Council - MR/T028254/1Funding
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.
Funders | Funder number |
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Department of Life Sciences | |
Medical Research Council | MR/T028254/1 |
Biotechnology and Biological Sciences Research Council | BB/R017956/1 |
Cancer Research UK | A26941 |
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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1/07/23 → 30/06/26
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Biotechnology and Biological Sciences Research Council
1/10/18 → 30/06/22
Project: Research council