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

ABSTRACT: Summary 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-O-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 [KD] = 0.2 versus 9.7 nM), with 8 residues at the

SUBMITTER: Brennan A 

PROVIDER: S-EPMC9582194 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature