Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases
Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases
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DOI：
10.1021/jm301557k
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发表时间：
2013-04-11
影响因子：
7.3
通讯作者：
Valenzano, Kenneth J.
中科院分区：
文献类型：
--
作者：
Boyd, Robert E.;Lee, Gary;Valenzano, Kenneth J.
溶酶体酶负责降解多种糖脂、寡糖、蛋白质和糖蛋白。编码这些蛋白质的基因中的遗传突变可导致新合成的溶酶体酶的稳定性降低。虽然通常具有催化活性，但突变的酶不能有效地通过内质网的质量控制机制，导致溶酶体运输、底物积累和细胞功能障碍减少。药理学伴侣（PC）是结合和稳定突变体溶酶体酶的小分子，从而允许适当的细胞易位。在许多临床前模型和临床研究中，此类化合物已显示出增加酶活性并降低底物负荷。在这个角度来看，我们回顾了几个溶酶体疾病的PC已被研究和SAR的各类分子。
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.