title: Peptides to peptidomimetics: towards the design and synthesis of bioavailable inhibitors of oligosaccharyl transferase.
abstract: Oligosaccharyl transferase (OT) is the enzyme responsible for asparagine-linked glycosylation in the lumen of the endoplasmic reticulum, which is a subcellular compartment within eukaryotic cells. Inhibition of this enzyme within a cellular environment would provide a valuable investigative tool for glycobiology. Due to the limitations of peptides, none of the existing peptide-based inhibitors of OT demonstrate activity in cell-based enzyme assays. We report herein the design, synthesis and preliminary biological characterization of a family of peptidomimetics that inhibit OT with Ki values in the nanomolar range. The hexapeptide Bz-Dab-Ala-Thr-Val-Thr-Nph-NH2 (Ki = 69 nM) was used as the prototype for the design of bioavailable inhibitors. Several aminobenzoic acid spacer groups were evaluated as potential isosteres of the Val-Thr dipeptide unit and the peptidomimetic incorporating 3-aminobenzoic acid proved to inhibit OT with similar potency to the parent compound (Ki = 84 nM). Further modifications explored the effects of size, hydrophobicity and conformational rigidity on enzyme affinity. This study yielded a family of potent non-peptidic inhibitors that are viable candidates for the in vivo inhibition of OT.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.forename: Barbara
authors.initials: B
authors.lastname: Imperiali
mesh_terms: D001216:Asparagine / Q000737:chemistry; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins; D008956:Models, Chemical; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010455:Peptides; D001216:Asparagine; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase