title: Synthetic 1-deoxynojirimycin N-substituted peptides offer prolonged disruption to N-linked glycan processing.
abstract: A panel of 1-deoxynojirimycin (DNJ) N-linked peptides were synthesized. Their IC50 values were measured in vitro against α-glucosidases I and II and were found to be in the micromolar range for both isozymes, and better than that of the iminosugar NB-DNJ (miglustat, 3) against α-glucosidase II. Cell-based studies revealed that although the free iminosugar 3 is most effective at disrupting N-linked glycan processing for short-term incubations (one day), when the cell-based studies were extended to three days, the DNJ N-linked tetrapeptide KDEL, which is an endoplasmic reticulum (ER)-retaining sequence, performed far better than 3. In low inhibitor washout studies, NB-DNJ inhibition was decreased to zero after 24 h, but DNJ-KDEL retained 13  % activity. This method offers a general approach for targeting drugs to the ER and prolonging their activity. Moreover, it is modular, so as new iminosugars of increased potency are discovered, they can be added to this template for targeting.
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK).
authors.forename: Aimé López
authors.initials: AL
authors.lastname: Aguilar
authors.forename: Jaime
authors.initials: J
authors.lastname: Escribano
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry; D006031:Glycosylation; D050111:Imino Sugars / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
chemical_list: C478924:1-deoxy-nojirimycin; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D010455:Peptides; D011134:Polysaccharides; D000520:alpha-Glucosidases; D005944:Glucosamine; D009584:Nitrogen
keywords: cell targeting; glycosidases; iminosugars; inhibitors; peptide conjugates