title: Stapling of a 3(10)-helix with click chemistry.
abstract: 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 3(10)- and α-helical peptides. However, atomic resolution structural information on the effect of side chain-to-side chain cyclization in 3(10)-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 3(10)-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 3(10)-helix than its acyclic precursor and other stapled 3(10)-helical peptides reported to date. Side chain-to-side chain stapling by CuAAC should prove useful when applied to 3(10)-helical peptides and protein segments of interest in biomedicine.
authors.affiliation: School of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316 Oslo, Norway. oyvind.jacobsen@farmasi.uio.no
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Jacobsen
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maekawa
authors.forename: Nien-Hui
authors.initials: NH
authors.lastname: Ge
authors.forename: Carl Henrik
authors.initials: CH
authors.lastname: Görbitz
authors.forename: Pål
authors.initials: P
authors.lastname: Rongved
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Mahmood
authors.initials: M
authors.lastname: Amiry-Moghaddam
authors.forename: Jo
authors.initials: J
authors.lastname: Klaveness
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000621:Aminoisobutyric Acids / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D002384:Catalysis; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000480:Alkynes; D000621:Aminoisobutyric Acids; D001386:Azides; D010455:Peptides; C100049:2-aminoisobutyric acid; D003300:Copper