Abstract
Hydrocarbon stapling is a useful tool for stabilizing the secondary structure of peptides. Among several methods, hydrocarbon stapling at i,i + 1 positions was not extensively studied, and their secondary structures are not clarified. In this study, we investigate i,i + 1 hydrocarbon stapling between cis-4-allyloxy-l-proline and various olefin-tethered amino acids. Depending on the ring size of the stapled side chains and structure of the olefin-tethered amino acids, E- or Z-selectivities were observed during the ring-closing metathesis reaction (E/Z was up to 8.5:1 for 17–14-membered rings and up to 1:20 for 13-membered rings). We performed X-ray crystallographic analysis of hydrocarbon stapled peptide at i,i + 1 positions. The X-ray crystallographic structure suggested that the i,i + 1 staple stabilizes the peptide secondary structure to the right-handed α-helix. These findings are especially important for short oligopeptides because the employed stapling method uses two minimal amino acid residues adjacent to each other.
Highlights
Introducing hydrocarbon stapling on the side chains of peptides is a promising technique for stabilizing the secondary structure of peptides and enhancing their functionalities [1,2,3,4,5]
Hydrocarbon stapling can be obtained by ring-closing metathesis reactions between olefin-bearing amino acid residues using Ru catalysts [6,7]
In this study, we started by optimizing bearing amino acid for peptide stapling [19]
Summary
Introducing hydrocarbon stapling on the side chains of peptides is a promising technique for stabilizing the secondary structure of peptides and enhancing their functionalities [1,2,3,4,5]. Hydrocarbon stapling can be obtained by ring-closing metathesis reactions between olefin-bearing amino acid residues using Ru catalysts [6,7]. L-serines at i,i + 3 positions to produce 310 -helical peptides [13]. Other hydrocarbon staples, such as i,i + 1 and i,i + 2, were not well researched, and their 3D structures are unknown (as illustrated in Figure 1b) [16,17,18,19]. We report hydrocarbon stapling of peptides at i,i + 1 positions by ring-closing metathesis reactions and the X-ray crystallographic structure of the right-handed α-helical octapeptide stabilized by i,i + 1 stapling.
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