Structure · dataset · 2026
De Novo Discovery of Cysteine-Targeted Reversible Covalent Cyclic Peptides with Prolonged Residence Time via Phage Display
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Reversible covalent targeting of cysteine residues offers a powerful strategy for generating potent and tunable ligands, but designing electrophiles with balanced reactivity, stability, and reversible binding remains challenging.
Description
Here, we systematically optimized reversible α,β-unsaturated nitrile electrophiles and incorporated the selected warhead with prolonged residence time into phage-displayed peptides to construct a library of reversible covalent cyclic peptides.
Screening this library against Keap1 enabled the de novo identification of ligands with nanomolar affinities, demonstrating a 5–100-fold improvement in binding potency relative to the corresponding noncovalent cyclic peptides. The most potent ligand, cyclic peptide <b>32</b>, exhibits a <i>K</i><sub>i</sub> of 3.7 nM, retains binding under thiol-rich conditions, and can capture Keap1 from a complex cellular environment.
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Mechanistic analysis reveals that peptide-mediated targeting in cyclic peptide <b>32</b> positions the reversible covalent warhead to react rapidly with Keap1 Cys434 while maintaining prolonged residence, allowing covalent bond formation to keep pace with the transient binding dynamics of the peptide–protein interaction. Overall, this work establishes a general strategy for integrating tunable reversible covalent chemistry into genetically encoded peptide libraries, enabling de novo discovery of high-affinity ligands.
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Where it is published
- DOI doi.org/10.1021/jacs.6c17599.s001 ↗
DOI / persistent id · from zivahub uct ac za
Catalogue records · 1
- OAI-PMH record api.figshare.com/v2/oai?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Af… ↗
metadata API · from zivahub uct ac za
Topics
- From keywords
- Biochemistry and cell biology · Cancer · Chemistry · Earth & Environmental Science · Inorganic chemistry · Life Sciences · Medicine & Health
Provenance · 1 source records, 12 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| ZivaHub | oai:figshare.com:article/34018695 | 9 d ago | JSON v1 |
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| concepts[field].anzsrc:group:3101 | mapping · zivahub uct ac za | vocabulary-mapper@1.0.0 | keywords['Cell Biology'] |
| concepts[field].anzsrc:group:3402 | mapping · zivahub uct ac za | vocabulary-mapper@1.0.0 | keywords['Inorganic Chemistry'] |
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| license | source · zivahub uct ac za | connector:zivahub_uct_ac_za@1.0.0 | /metadata/dc/rights |
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| title | source · zivahub uct ac za | connector:zivahub_uct_ac_za@1.0.0 | /metadata/dc/title |