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

Brennan, Andrew, Leech, James T, Kad, Neil M, Mason, Jody M (2022) The effect of helix-inducing constraints and downsizing upon a transcription block survival-derived functional cJun antagonist. Cell reports. Physical science, 3 (10). Article Number 101077. E-ISSN 2666-3864. (doi:10.1016/j.xcrp.2022.101077) (KAR id:98289)


Inhibition of cJun is established as a promising therapeutic approach, particularly in cancer. We recently developed the "transcription block survival" (TBS) screening platform to derive functional peptide antagonists of transcription factor activity by ablating their ability to bind to cognate DNA. Using TBS, we screened a >131,000-member peptide library to select a 63-mer peptide that bound cJun and prevented 12-<i>O</i>-tetradecanoylphorbol-13-acetate response element (TRE) DNA binding. Iterative truncation was next combined with a systematic exploration of side-chain cyclization to derive a minimal active sequence. The resulting dual lactamized sequence was >40% smaller and retained low nM target affinity (equilibrium binding constant [<i>K</i> <sub><i>D</i></sub> ] = 0.2 versus 9.7 nM), with 8 residues at the acidic region required for functional antagonism. However, even modest C-terminal truncation resulted in functional loss. The peptide functionally antagonizes cJun (half-maximal inhibitory concentration [IC<sub>50</sub>] = 13 versus 45 μM) and is considerably more stable in human serum relative to its non-lactamized counterpart and HingeW.

Item Type: Article
DOI/Identification number: 10.1016/j.xcrp.2022.101077
Additional information: For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. ** From Europe PMC via Jisc Publications Router ** History: ppub 01-10-2022; epub 19-10-2022. ** Licence for this article: cc by
Uncontrolled keywords: Transcription factor, Activator protein-1, protein-protein interactions, Peptide Antagonist, Cjun, Peptide Cyclization, Transcription Block Survival, Functional Antagonists
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Cancer Research UK (
Medical Research Council (
Biotechnology and Biological Sciences Research Council (
SWORD Depositor: JISC Publications Router
Depositing User: JISC Publications Router
Date Deposited: 28 Nov 2022 11:11 UTC
Last Modified: 20 Nov 2023 15:41 UTC
Resource URI: (The current URI for this page, for reference purposes)

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