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首页> 外文期刊>International journal of clinical pharmacology and therapeutics >Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies
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Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies

机译：活性部位特异性伴侣在法布里病中的药理伴侣疗法：体外和临床前研究

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Many genetic disorders are due to protein misfolding and excessive premature degradation in the endoplasmic reticu-lum (ER). When a gene mutation does not affect the functionality of the protein, it may still promote the premature clearance of the protein by ER-associated degradation (ERAD), resulting in a loss of function. Competitive inhibitors are often effective active-site-specific chaperones when used at sub-inhibitory concentrations. Active-site-specific chaperones assist in the folding of mutant lysosomal enzymes in the ER, thereby promoting their escape from ERAD, enhancing trafficking to the lysosome and increasing the level of residual enzyme activity. In Fabry disease, degradation of various mutant forms of ot-galactosidase A (a-gal A) has been shown to take place in the ER as a result of protein misfolding. One of the most potent inhibitors of a-gal A, 1-deoxygalactonojirimycin, has also been shown to be effective in enhancing residual a-gal A activity in cultured fibro-blasts and lymphoblasts established from patients with Fabry disease caused by a variety of missense mutations. Oral administration of 1-deoxygalactonojirimycin to trans-genic mice expressing a mutant form of human a-gal A (R301Q) yielded higher a-gal A activity in major tissues, compared with untreated transgenic mice.dominique.germain@rpc.aphp.fr
机译：许多遗传疾病是由于蛋白质错误折叠和内质网（ER）中的过早降解所致。当基因突变不影响蛋白质的功能时，它仍可能通过ER相关降解（ERAD）促进蛋白质的过早清除，从而导致功能丧失。当以亚抑制浓度使用时，竞争性抑制剂通常是有效的活性位点特异性伴侣。活性位点特异性伴侣蛋白有助于内质网中突变的溶酶体酶的折叠，从而促进它们从ERAD逃逸，增强向溶酶体的运输并增加残留酶活性的水平。在法布里疾病中，已证明由于蛋白质错误折叠，内质网中发生了各种突变形式的半乳糖苷酶A（α-galA）降解。 α-galA的最有效抑制剂之一，即1-脱氧半乳糖苷霉素，已被证明可有效增强由多种错觉引起的法布里氏病患者建立的培养的成纤维细胞和淋巴母细胞中残留的a-gal A活性。突变。与未处理的转基因小鼠相比，对表达人a-gal A突变体（R301Q）的转基因小鼠口服1-deoxygalactonojirimycin产生较高的a-gal A活性。dominique.germain@ rpc.aphp.fr

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