Biology

Photoredox-Mediated Peptide Stapling Enables Selective Protein-Protein Interaction Inhibitors

Context

Peptide-based therapeutics face significant challenges including poor cell permeability, rapid degradation by proteases, and loss of bioactive conformations. Stapled peptides—where side chains are covalently linked—can address these limitations, but existing stapling methods often require pre-functionalized amino acids and harsh coupling conditions that limit sequence compatibility.

What's New

This work demonstrates that visible-light photoredox catalysis can mediate direct C-H alkylation between native amino acid side chains, forming all-hydrocarbon staples in one step. Using an organic photocatalyst and mild conditions, the method works on unprotected peptides in aqueous buffer. The stapled peptides show 10-100 fold improvements in cellular uptake and proteolytic stability compared to linear counterparts.

Why It Matters

This methodology dramatically simplifies access to stapled peptide therapeutics, potentially accelerating development timelines for difficult-to-drug targets like protein-protein interactions. The compatibility with native sequences and aqueous conditions suggests immediate utility for academic and pharmaceutical research. Early results with MDM2-p53 inhibitors demonstrate promising in vivo stability and efficacy.

Limitations & Open Questions

Current yields are moderate (30-50%) and the method works best with specific amino acid pairs (primarily tyrosine and phenylalanine). Stereocontrol remains imperfect, often producing mixtures of diastereomers. The approach has not yet been validated on larger proteins or more complex biological matrices. Scale-up beyond milligram quantities requires further development.
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References

Cell Chemical Biology (2023)

DOI: 10.1016/j.cell.2023.05.012

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