title: N-linked glycosylated beta-peptides are resistant to degradation by glycoamidase A.
abstract: Beta-peptides are resistant to degradation by a variety of proteolytic enzymes that rapidly degrade natural alpha-peptides. This is one of many characteristics that make beta-peptides an attractive class of compounds for drug discovery efforts. To further understand the molecular recognition properties of beta-peptides and the ability of enzymes to degrade them, we have synthesized a series of N-linked glycosylated beta- and alpha-peptides, and tested their stability towards a glycosidase. We found that glyco-beta-peptides that contain N-acetylglucosamine (1) or N,N-diacetylchitobiose (2) are completely stable to degradation by glycoamidase A. In comparison, the glyco-alpha-peptides 3 and 4 containing N-acetylglucosamine or N,N-diacetylchitobiose are degraded. Inhibition experiments using increasing concentrations of a glyco-beta-peptide fail to inhibit degradation of the corresponding glyco-alpha-peptide, even when the glyco-beta-peptide is at a 128-fold higher concentration than the glyco-alpha-peptide. Evidently, the glyco-beta-peptides have a much weaker affinity for the active site of the glycosidase than the corresponding glyco-alpha-peptide. These and the results with proteolytic enzymes suggest that the additional CH(2) group introduced into the alpha-amino acid residues causes beta-peptides not to be recognized by hydrolytic enzymes. The results described herein suggest the potential of beta-peptides that are functionalized with carbohydrates for biological and biomedical investigations, without having to be concerned about the carbohydrate being removed.
authors.affiliation: Laboratorium für Organische Chemie, Department für Chemie und Angewandte Biowissenschaften, Eidgenössische Technische Hochschule Zürich, ETH Hönggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
authors.forename: David F
authors.initials: DF
authors.lastname: Hook
authors.forename: Kenji
authors.initials: K
authors.lastname: Namoto
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry* / Q000378:metabolism*; D004351:Drug Resistance; D006020:Glycopeptides / Q000378:metabolism*; D006031:Glycosylation; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D006020:Glycopeptides; D010446:Peptide Fragments; D000581:Amidohydrolases