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

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 310helices. Circular dichroism spectroscopy revealed that the Ri,i & thorn;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.