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An Approach to Derive Functional Peptide Inhibitors of Transcription Factor Activity

Brennan, Andrew, Leech, James T., Kad, Neil M., Mason, Jody M. (2022) An Approach to Derive Functional Peptide Inhibitors of Transcription Factor Activity. JACS Au, 2 (4). pp. 996-1006. E-ISSN 2691-3704. (doi:10.1021/jacsau.2c00105) (KAR id:95697)


We report the development of a high-throughput, intracellular "transcription block survival" (TBS) screening platform to derive functional transcription factor antagonists. TBS is demonstrated using the oncogenic transcriptional regulator cJun, with the development of antagonists that bind cJun and prevent both dimerization and, more importantly, DNA binding remaining a primary challenge. In TBS, cognate TRE sites are introduced into the coding region of the essential gene, dihydrofolate reductase (DHFR). Introduction of cJun leads to TRE binding, preventing DHFR expression by directly blocking RNA polymerase gene transcription to abrogate cell proliferation. Peptide library screening identified a sequence that both binds cJun and antagonizes function by preventing DNA binding, as demonstrated by restored cell viability and subsequent in vitro hit validation. TBS is an entirely tag-free genotype-to-phenotype approach, selecting desirable attributes such as high solubility, target specificity, and low toxicity within a complex cellular environment. TBS facilitates rapid library screening to accelerate the identification of therapeutically valuable sequences.

Item Type: Article
DOI/Identification number: 10.1021/jacsau.2c00105
Uncontrolled keywords: transcription block survival peptide antagonists transcription factors activator protein-1 library screening
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Neil Kad
Date Deposited: 07 Jul 2022 09:55 UTC
Last Modified: 08 Jul 2022 08:25 UTC
Resource URI: (The current URI for this page, for reference purposes)

University of Kent Author Information

Leech, James T..

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Kad, Neil M..

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