Stapling of a 310-Helix with Click Chemistry

• Published in: Journal of organic chemistry Vol. 76; no. 5; pp. 1228 - 1238
• Main Authors: Jacobsen, Øyvind, Maekawa, Hiroaki, Ge, Nien-Hui, Görbitz, Carl Henrik, Rongved, Pål, Ottersen, Ole Petter, Amiry-Moghaddam, Mahmood, Klaveness, Jo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 04.03.2011
• Subjects: Chemistry; Exact sciences and technology; Organic chemistry; Peptides; Preparations and properties; Structure effect; Acetylenic compound; Cyclic peptides; Metathesis; NMR spectrometry; Molecular probe; Helical structure; Copper; Femtosecond; Drug; Molecular flexibility; Catalytic reaction; Enzyme; Organic azide; Transition metal; X ray diffraction; Biological activity; Protein; Two dimension spectrometry; Isobutyric acid; Infrared spectrometry; Azides; In vivo; Peptidases; Cycloaddition; Side chain; Copper ion; Olefin; Cyclization; Hydrolases; Ethylenic compound; Alkyne; Conformation
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo101670a

Short peptides are important as lead compounds and molecular probes in drug discovery and chemical biology, but their well-known drawbacks, such as high conformational flexibility, protease lability, poor bioavailability and short half-lives in vivo, have prevented their potential from being fully realized. Side chain-to-side chain cyclization, e.g., by ring-closing olefin metathesis, known as stapling, is one approach to increase the biological activity of short peptides that has shown promise when applied to 310- and α-helical peptides. However, atomic resolution structural information on the effect of side chain-to-side chain cyclization in 310-helical peptides is scarce, and reported data suggest that there is significant potential for improvement of existing methodologies. Here, we report a novel stapling methodology for 310-helical peptides using the copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction in a model aminoisobutyric acid (Aib) rich peptide and examine the structural effect of side chain-to-side chain cyclization by NMR, X-ray diffraction, linear IR and femtosecond 2D IR spectroscopy. Our data show that the resulting cyclic peptide represents a more ideal 310-helix than its acyclic precursor and other stapled 310-helical peptides reported to date. Side chain-to-side chain stapling by CuAAC should prove useful when applied to 310-helical peptides and protein segments of interest in biomedicine.