Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases

被引:172
作者
Boyd, Robert E. [1 ]
Lee, Gary [1 ]
Rybczynski, Philip [1 ]
Benjamin, Elfrida R. [1 ]
Khanna, Richie [1 ]
Wustman, Brandon A. [2 ]
Valenzano, Kenneth J. [1 ]
机构
[1] Amicus Therapeut, Cranbury, NJ 08512 USA
[2] Amicus Therapeut, La Jolla, CA 92037 USA
关键词
ALPHA-GALACTOSIDASE-A; ENZYME REPLACEMENT THERAPY; OCTYL-BETA-VALIENAMINE; GAUCHER-DISEASE; FABRY-DISEASE; POMPE-DISEASE; CHEMICAL CHAPERONES; BIOLOGICAL EVALUATION; GLUCOCEREBROSIDASE INHIBITORS; ISOFAGOMINE INCREASES;
D O I
10.1021/jm301557k
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules.
引用
收藏
页码:2705 / 2725
页数:21
相关论文
共 123 条
[1]   Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase [J].
Aguilar-Moncayo, Matilde ;
Isabel Garcia-Moreno, M. ;
Trapero, Ana ;
Egido-Gabas, Meritxell ;
Llebaria, Amadeu ;
Garcia Fernandez, Jose M. ;
Ortiz Mellet, Carmen .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2011, 9 (10) :3698-3713
[2]   Miglustat (NB-DNJ) works as a chaperone for mutated acid β-glucosidase in cells transfected with several Gaucher disease mutations [J].
Alfonso, P ;
Pampín, S ;
Estrada, J ;
Rodríguez-Rey, JC ;
Giraldo, P ;
Sancho, J ;
Pocoví, M .
BLOOD CELLS MOLECULES AND DISEASES, 2005, 35 (02) :268-276
[3]   In vitro inhibition and intracellular enhancement of lysosomal α-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives [J].
Asano, N ;
Ishii, S ;
Kizu, H ;
Ikeda, K ;
Yasuda, K ;
Kato, A ;
Martin, OR ;
Fan, JQ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2000, 267 (13) :4179-4186
[4]  
Ashton-Prolla P, 2000, J INVEST MED, V48, P227
[5]   Emerging drugs for lysosomal storage diseases [J].
Beck, Michael .
EXPERT OPINION ON EMERGING DRUGS, 2010, 15 (03) :495-507
[6]  
Beck Michael, 2009, Ther Clin Risk Manag, V5, P767
[7]   Lysosomal storage diseases and the blood-brain barrier [J].
Begley, David J. ;
Pontikis, Charles C. ;
Scarpa, Maurizio .
CURRENT PHARMACEUTICAL DESIGN, 2008, 14 (16) :1566-1580
[8]   The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines [J].
Benjamin, E. R. ;
Flanagan, J. J. ;
Schilling, A. ;
Chang, H. H. ;
Agarwal, L. ;
Katz, E. ;
Wu, X. ;
Pine, C. ;
Wustman, B. ;
Desnick, R. J. ;
Lockhart, D. J. ;
Valenzano, K. J. .
JOURNAL OF INHERITED METABOLIC DISEASE, 2009, 32 (03) :424-440
[9]   Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice [J].
Benjamin, Elfrida R. ;
Khanna, Richie ;
Schilling, Adriane ;
Flanagan, John J. ;
Pellegrino, Lee J. ;
Brignol, Nastry ;
Lun, Yi ;
Guillen, Darlene ;
Ranes, Brian E. ;
Frascella, Michelle ;
Soska, Rebecca ;
Feng, Jessie ;
Dungan, Leo ;
Young, Brandy ;
Lockhart, David J. ;
Valenzano, Kenneth J. .
MOLECULAR THERAPY, 2012, 20 (04) :717-726
[10]  
Beutler E., 2001, METABOLIC MOL BASES, V3, P3635