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)
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Official URL: https://doi.org/10.1016/j.xcrp.2022.101077 |
Abstract
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 |
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DOI/Identification number: | 10.1016/j.xcrp.2022.101077 |
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 (https://ror.org/054225q67)
Medical Research Council (https://ror.org/03x94j517) Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982) |
SWORD Depositor: | JISC Publications Router |
Depositing User: | JISC Publications Router |
Date Deposited: | 28 Nov 2022 11:11 UTC |
Last Modified: | 18 Jul 2024 10:06 UTC |
Resource URI: | https://kar.kent.ac.uk/id/eprint/98289 (The current URI for this page, for reference purposes) |
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