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

• Published in: Bioorganic & medicinal chemistry 2024-11, Vol.114, p.117963, Article 117963
• Main Authors: Tran, Duc V.H., Nguyen, Ha T.N., Ahn, Hee-Chul, Kim, Young-Woo
• Format: Article
• Language: English
• Subjects: 310-Helix; Hydrocarbon staples; Peptide conformation; Proteinogenic peptides; Screw sense control
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117963

[Display omitted] •Novel 4-atom hydrocarbon staple stabilizes 310-helices in proteinogenic peptides.•Staple configuration controls both helix stabilization and screw sense in 310-helical peptides.•Multiple 4-atom staples enhance stability of 310-helices in longer peptide sequences. 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.