title: Dynamic covalent side-chain cross-links via intermolecular oxime or hydrazone formation from bifunctional peptides and simple organic linkers.
abstract: Peptide cyclization via chemoselective reactions between side chains has proven a useful strategy to control folded structure. We report here a method for the synthesis of side-chain to side-chain cyclic peptides based on the intermolecular reaction between a linear peptide functionalized with two aminooxy or hydrazide side chains and an organic dialdehyde linker. A family of oxime-based and hydrazone-based cyclic products is prepared in a modular and convergent fashion by combination of unprotected linear peptide precursors and various small molecule linkers in neutral aqueous buffer. The side-chain to side-chain linkages that result can alter peptide folding behavior. The dynamic covalent nature of the Schiff bases in the cyclic products can be utilized to create mixtures where product composition changes in response to experimental conditions. Thus, a linear peptide precursor can select one organic linker from a mixture, and a cyclic product can dynamically exchange the small molecule component of the macrocycle.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Conor M
authors.initials: CM
authors.lastname: Haney
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: W Seth
authors.initials: WS
authors.lastname: Horne
mesh_terms: D000595:Amino Acid Sequence; D060326:Chemistry Techniques, Synthetic; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003500:Cyclization; D006835:Hydrazones / Q000737:chemistry*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D012545:Schiff Bases / Q000737:chemistry
chemical_list: D003432:Cross-Linking Reagents; D006835:Hydrazones; D010091:Oximes; D010455:Peptides; D010456:Peptides, Cyclic; D012545:Schiff Bases
keywords: Schiff bases; cyclic peptides; dynamic covalent chemistry; peptide staples