Stapled Peptides by Late-Stage C(sp³ )-H Activation

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Stapled peptides are crucial for drug discovery, but limited preparation methods restrict staple motif diversity.
• C-H activation offers efficient molecular functionalization, yet post-synthetic peptide C-H modification, especially C(sp3)-H, is underexplored.

Purpose of the Study:

• To develop a novel palladium-catalyzed late-stage C(sp3)-H activation method for peptide stapling.
• To create unprecedented hydrocarbon cross-links and expand the structural diversity of stapled peptides.

Main Methods:

• Development of a palladium-catalyzed late-stage C(sp3)-H activation strategy.
• Application of the method for synthesizing a library of stapled peptides in solution.
• Investigation of compatibility with diverse amino acids and staple parameters (size and length).

Main Results:

• Successful implementation of a novel C(sp3)-H activation for peptide stapling, yielding unique hydrocarbon cross-links.
• Demonstrated compatibility with various amino acids and explored the impact of staple size (i,i+3, i,i+4) and length.
• Established a facile solid-phase synthesis procedure for stapled peptides.

Conclusions:

• The developed method provides a new avenue for synthesizing structurally diverse stapled peptides.
• This approach broadens the utility of C-H activation in peptide modification and drug discovery.
• The established solid-phase procedure facilitates scalable production of novel stapled peptide therapeutics.