310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples

Duc V.H. Tran, Ha T.N. Nguyen, Hee Chul Ahn, Young Woo Kim

Research output: Contribution to journalArticlepeer-review

Abstract

The 310-helix is a crucial secondary structure in proteins, playing an essential role in various protein–protein interactions, yet stabilizing it in biologically relevant peptides remains challenging. In this study, we investigated the potential of 4-atom hydrocarbon staples to stabilize 310-helices in peptides. Using ring-closing metathesis, we demonstrated that the staple's configuration is critical for both the stabilization and screw sense control of 310-helices. Circular dichroism spectroscopy revealed that the Ri,i+3S(4) staple—a 4-atom cross-link with (R)-configuration at the i position, (S)-configuration at the i + 3 position, and flanked by methyl groups—strongly induces right-handed 310-helices, especially in sequences with proteinogenic L-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.

Original languageEnglish
Article number117963
JournalBioorganic and Medicinal Chemistry
Volume114
DOIs
StatePublished - 15 Nov 2024

Keywords

  • 3-Helix
  • Hydrocarbon staples
  • Peptide conformation
  • Proteinogenic peptides
  • Screw sense control

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