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Synthetic 1‐Deoxynojirimycin N‐Substituted Peptides Offer Prolonged Disruption to N‐Linked Glycan Processing
Author(s) -
Aguilar Aimé López,
Escribano Jaime,
Wentworth Paul,
Butters Terry D.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402186
Subject(s) - iminosugar , glycan , glucosidases , chemistry , endoplasmic reticulum , kdel , biochemistry , in vitro , pharmacology , enzyme , biology , golgi apparatus , glycoprotein
A panel of 1‐deoxynojirimycin (DNJ) N‐linked peptides were synthesized. Their IC 50 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 N B‐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, N B‐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.