A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity

被引:124
作者
Fan, Jian-Qiang [1 ]
机构
[1] Mt Sinai Hosp, Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA
关键词
active-site-specific chaperone; endoplasmic reticulum-associated degradation; enzyme inhibitor; lysosomal storage disorders; pharmacological chaperone; protein misfolding;
D O I
10.1515/BC.2008.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pharmacological chaperone therapy is an emerging counterintuitive approach to treat protein deficiencies resulting from mutations causing misfolded protein conformations. Active-site-specific chaperones (ASSCs) are enzyme active-site directed small molecule pharmacological chaperones that act as a folding template to assist protein folding of mutant proteins in the endoplasmic reticulum (ER). As a result, excessive degradation of mutant proteins in the ER-associated degradation (ERAD) machinery can be prevented, thus restoring enzyme activity. Lysosomal storage disorders (LSDs) are suitable candidates for ASSC treatment, as the levels of enzyme activity needed to prevent substrate storage are relatively low. In addition, ASSCs are orally active small molecules and have potential to gain access to most cell types to treat neuronopathic LSDs. Competitive enzyme inhibitors are effective ASSCs when they are used at sub-inhibitory concentrations. This whole new paradigm provides excellent opportunity for identifying specific drugs to treat a broad range of inherited disorders. This review describes protein misfolding as a pathophysiological cause in LSDs and provides an overview of recent advances in the development of pharmacological chaperone therapy for the diseases. In addition, a generalized guidance for the design and screening of ASSCs is also presented.
引用
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页码:1 / 11
页数:11
相关论文
共 68 条
[1]   NAGSTATIN, A NEW INHIBITOR OF N-ACETYL-BETA-D-GLUCOSAMINIDASE, PRODUCED BY STREPTOMYCES-AMAKUSAENSIS MG846-FF3 - TAXONOMY, PRODUCTION, ISOLATION, PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL-ACTIVITIES [J].
AOYAGI, T ;
SUDA, H ;
UOTANI, K ;
KOJIMA, F ;
AOYAMA, T ;
HORIGUCHI, K ;
HAMADA, M ;
TAKEUCHI, T .
JOURNAL OF ANTIBIOTICS, 1992, 45 (09) :1404-1408
[2]   MANNOSTATIN-A AND MANNOSTATIN-B - NEW INHIBITORS OF ALPHA-D-MANNOSIDASE, PRODUCED BY STREPTOVERTICILLIUM-VERTICILLUS VAR QUINTUM ME3-AG3 - TAXONOMY, PRODUCTION, ISOLATION, PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL-ACTIVITIES [J].
AOYAGI, T ;
YAMAMOTO, T ;
KOJIRI, K ;
MORISHIMA, H ;
NAGAI, M ;
HAMADA, M ;
TAKEUCHI, T ;
UMEZAWA, H .
JOURNAL OF ANTIBIOTICS, 1989, 42 (06) :883-889
[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]   N-CONTAINING SUGARS FROM MORUS-ALBA AND THEIR GLYCOSIDASE INHIBITORY ACTIVITIES [J].
ASANO, N ;
OSEKI, K ;
TOMIOKA, E ;
KIZU, H ;
MATSUI, K .
CARBOHYDRATE RESEARCH, 1994, 259 (02) :243-255
[5]   Novel α-L-fucosidase inhibitors from the bark of Angylocalyx pynaertii (Leguminosae) [J].
Asano, N ;
Yasuda, K ;
Kizu, H ;
Kato, A ;
Fan, JQ ;
Nash, RJ ;
Fleet, GWJ ;
Molyneux, RJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (01) :35-41
[6]   Homonojirimycin isomers and glycosides from Aglaonema treubii [J].
Asano, N ;
Nishida, M ;
Kizu, H ;
Matsui, K ;
Watson, AA ;
Nash, RJ .
JOURNAL OF NATURAL PRODUCTS, 1997, 60 (02) :98-101
[7]   Pharmacological chaperones:: potential treatment for conformational diseases [J].
Bernier, V ;
Lagacé, M ;
Bichet, DG ;
Bouvier, M .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2004, 15 (05) :222-228
[8]  
Beutler E., 2001, METABOLIC MOL BASES, V3, P3635
[9]   ENZYMATIC DEFECT IN FABRYS DISEASE - CERAMIDETRIHEXOSIDASE DEFICIENCY [J].
BRADY, RO ;
GAL, AE ;
BRADLEY, RM ;
MARTENSS.E ;
WARSHAW, AL ;
LASTER, L .
NEW ENGLAND JOURNAL OF MEDICINE, 1967, 276 (21) :1163-&
[10]   METABOLISM OF GLUCOCEREBROSIDES .2. EVIDENCE OF AN ENZYMATIC DEFICIENCY IN GAUCHERS DISEASE [J].
BRADY, RO ;
KANFER, JN ;
SHAPIRO, D .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1965, 18 (02) :221-&