Synthetic 1-Deoxynojirimycin N-Substituted Peptides Offer Prolonged Disruption to N-Linked Glycan Processing

被引：3

作者：

Aguilar, Aime Lopez ^{[1
]}

Escribano, Jaime ^{[1
]}

Wentworth, Paul, Jr. ^{[1
,2
]}

Butters, Terry D. ^{[1
]}

机构：

[1] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England

[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

来源：

CHEMMEDCHEM | 2014年 / 9卷 / 12期

关键词：

cell targeting; glycosidases; iminosugars; inhibitors; peptide conjugates; CELL PENETRATING PEPTIDES; DRUG-DELIVERY; GLYCOSPHINGOLIPID BIOSYNTHESIS; GLYCOSIDASE INHIBITORS; ENDOPLASMIC-RETICULUM; BIOLOGICAL-ACTIVITY; IMINO SUGARS; GLUCOSIDASE; DEOXYNOJIRIMYCIN; PROTEIN;

D O I：

10.1002/cmdc.201402186

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A panel of 1-deoxynojirimycin (DNJ) N-linked peptides were synthesized. Their IC50 values were measured in vitro against -glucosidasesI 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 -glucosidaseII. 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 24h, 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.

引用

页码：2809 / 2813

页数：5

共 30 条

[1] Drug delivery systems: Entering the mainstream [J].

Allen, TM ;

Cullis, PR .

SCIENCE, 2004, 303 (5665) :1818-1822

[2] Glucosylated free oligosaccharides are biomarkers of endoplasmicreticulum α-glucosidase inhibition [J].

Alonzi, Dominic S. ;

Neville, David C. A. ;

Lachmann, Robin H. ;

Dwek, Raymond A. ;

Butters, Terry D. .

BIOCHEMICAL JOURNAL, 2008, 409 :571-580

[3] Sugar-mimic glycosidase inhibitors: natural occurrence, biological activity and prospects for therapeutic application [J].

Asano, N ;

Nash, RJ ;

Molyneux, RJ ;

Fleet, GWJ .

TETRAHEDRON-ASYMMETRY, 2000, 11 (08) :1645-1680

[4] Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-L-bulgecinine from D-glucuronolactone and of L-DNJ, L-DMDP, and (3S)-3-hydroxy-D-bulgecinine from L-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas L-DMDP is a potent and specific inhibitor of α-glucosidases [J].

Best, Daniel ;

Wang, Chen ;

Weymouth-Wilson, Alexander C. ;

Clarkson, Robert A. ;

Wilson, Francis X. ;

Nash, Robert J. ;

Miyauchi, Saori ;

Kato, Atsushi ;

Fleet, George W. J. .

TETRAHEDRON-ASYMMETRY, 2010, 21 (03) :311-319

[5] Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking [J].

Block, TM ;

Lu, XY ;

Mehta, AS ;

Blumberg, BS ;

Tennant, B ;

Ebling, M ;

Korba, B ;

Lansky, DM ;

Jacob, GS ;

Dwek, RA .

NATURE MEDICINE, 1998, 4 (05) :610-614

[6] Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis [J].

Butters, TD ;

van den Broek, LAGM ;

Fleet, GWJ ;

Krulle, TM ;

Wormald, MR ;

Dwek, RA ;

Platt, FM .

TETRAHEDRON-ASYMMETRY, 2000, 11 (01) :113-124

[7]

Compain P., 2007, IMINOSUGARS FROM SYN, P130

[8] GAUCHER'S DISEASE [J].

Dulsat, C. ;

Mealy, N. .

DRUGS OF THE FUTURE, 2009, 34 (02) :147-149

[9] Perturbation of free oligosaccharide trafficking in endoplasmic reticulum glucosidase I-deficient and castanospermine-treated cells [J].

Durrant, C ;

Moore, SEH .

BIOCHEMICAL JOURNAL, 2002, 365 :239-247

[10] Targeting glycosylation as a therapeutic approach [J].

Dwek, RA ;

Butters, TD ;

Platt, FM ;

Zitzmann, N .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (01) :65-75

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