Design and synthesis of highly potent and selective pharmacological chaperones for the treatment of Gaucher's disease
Design and synthesis of highly potent and selective pharmacological chaperones for the treatment of Gaucher's disease
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DOI：
10.1002/cbic.200600217
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发表时间：
2006-09-01
期刊：
影响因子：
3.2
通讯作者：
Asano, Naoki
中科院分区：
文献类型：
--
作者：
Compain, Philippe;Martin, Olivier R.;Asano, Naoki
化学伴侣方法是药物研究中的一个新兴概念，有望治疗由不正确折叠的蛋白质引起的遗传性疾病。[1]这一策略是基于某些低分子化合物稳定或改变缺陷蛋白质三维结构的能力。最近，化学伴侣的概念在溶酶体储存障碍领域被证明是有效的，溶酶体储存障碍是一组40多种罕见的疾病，其特征是参与溶酶体中鞘糖脂分解代谢的糖苷酶缺乏。[2]1999年，有报道称，法布里病患者的淋巴母细胞中残留的α半乳糖苷酶A活性可以通过在亚抑制浓度下使用基于亚氨糖的缺陷糖苷酶抑制剂来显著增强。[3]这种“非直观”的结果可以用以下事实来解释：即使有缺陷的酶容易折叠和/或不稳定，它仍然具有催化活性。[3D]可逆竞争抑制剂积极影响异常酶的折叠状态，从而通过质量控制防止其在内质网(ER)和内质网相关降解(ERAD)中降解，然后再转移到溶酶体。[4]根据所谓的阈值理论，[1，5]疾病的严重程度与患者溶酶体中残留的降解能力有关，因此，即使酶活性略有上升，也可以导致与溶酶体储存障碍相关的症状的显著改善。活性部位特异性伴侣策略正在进行临床评估，用于治疗Fabry病，从而突出了它们作为这些疾病的新治疗选择的强大潜力。最近的研究表明，这种方法可以应用于高谢病，最常见的溶酶体储存障碍。[6，7]这种常染色体隐性疾病是由葡萄糖神经酰胺β-葡萄糖苷酶，也称为β葡萄糖脑苷酶(GCASE)缺乏引起的，导致未降解的葡萄糖神经酰胺(GlcCer)积聚，特别是在巨噬细胞中，并出现严重的症状。[8]在类型1中，高谢病三种临床形式中最轻和最常见的一种，患者患有骨痛、骨骼病变、贫血和肝或脾损害。高谢病的一线治疗是基于给予谷氨酸氨基转移酶的重组形式Cerezyme来补充有缺陷的水解酶。[9]第二种策略利用小分子N-丁基-1-脱氧诺吉霉素1(NB-DNJ，Zavesca)来抑制GlcCer的生物合成。[10]尽管在治疗上取得了这些突破，但这两种方法都有不同的缺点。[9]酶替代疗法极其昂贵(每年超过150000美元)，而且只可能用于非神经病变的高雪氏症患者，因为这种酶不会越过血脑屏障。Zavesca只被推荐给患有轻到中度1型高谢病的成年人，而ERT对他们来说不是一个选择。需要大剂量(∼每天300毫克)，并会导致严重的副作用，包括腹痛和体重减轻，主要是由于抑制消化葡萄糖苷酶引起的。此外，Zavesca也是内质网处理葡萄糖苷酶I的强大抑制剂，葡萄糖苷酶I是一种关键的细胞糖苷酶，参与糖蛋白的糖链结构的阐述。[11]在寻找治疗高谢病的化学伴侣疗法中，Kelly等人。公开了将亚抑制浓度(10μm)的N-壬基-1-脱氧诺吉霉素(NN-DNJ，2)添加到成纤维细胞培养液中导致…
The chemical-chaperone approach is an emerging concept in drug research that holds promise for the treatment of inherited diseases caused by improperly folded proteins.[1] This strategy is based on the capacity of certain low-molecular-weight compounds to stabilize or alter the three-dimensional architecture of defective proteins. Recently, the effectiveness of the chemical-chaperone concept has been demonstrated in the field of lysosomal-storage disorders, a group of more than 40 rare diseases that are characterized by the deficiency of the glycosidases involved in the catabolism of glycosphingolipids in the lysosome.[2] In 1999, it was reported that the residual αgalactosidase A activity in the lymphoblasts of patients with Fabry disease could be significantly enhanced by using iminosugar-based inhibitors of the deficient glycosidase at subinhibitory concentrations.[3] This “nonintuitive” result can be explained by the fact that, even though the defective enzyme is predisposed to misfolding and/or instability, it is still catalytically active.[3d] Reversible competitive inhibitors positively influence the folding state of the abnormal enzyme, thus preventing its degradation by quality control in the endoplasmic reticulum (ER) and ER-associated degradation (ERAD) before its transfer to lysosomes.[4] According to the so-called threshold theory,[1, 5] the severity of the disease correlates with the residual degrading capacity in the patients’ lysosomes and, therefore, even a slight elevation in enzyme activity can lead to a significant improvement in the symptoms associated with a lysosomal-storage disorder. Active-site-specific chaperone strategies are being evaluated clinically for the treatment of Fabry disease, thus highlighting their strong potential as a new therapeutic option for these disorders. Recent studies have shown that this approach may be applied to Gaucher’s disease, the most prevalent lysosomal-storage disorder.[6, 7] This autosomal recessive disease is caused by a deficiency of glucosylceramide β-glucosidase, also called βglucocerebrosidase,(GCase) that leads to the accumulation of undegraded glucosylceramide (GlcCer), especially in macrophages, and to severe symptoms.[8] In type 1, the mildest and most common of the three clinical forms of Gaucher’s disease, patients suffer from bone pain, skeletal lesions, anaemia and liver or spleen damage. The first-line treatment for Gaucher’s disease is based on the administration of Cerezyme, a recombinant form of GCase, to supplement the defective hydrolytic enzyme.[9] A second strategy makes use of a small molecule, N-butyl-1-deoxynojirimycin 1 (NB-DNJ, Zavesca), to inhibit the biosynthesis of GlcCer.[10]Despite these therapeutic breakthroughs, both approaches possess various drawbacks.[9] Enzyme-replacement therapy (ERT) is extremely costly (over $150000 per year) and is only possible for non-neuronopathic Gaucher patients, since the enzyme does not cross the blood–brain barrier. Zavesca has been recommended only for adults with mild-to-moderate type 1 Gaucher’s disease for whom ERT is not an option. Large doses are required (∼ 300 mg daily) and lead to serious side effects including abdominal pains and loss of weight arising mainly from the inhibition of digestive glucosidases. Moreover, Zavesca is also a strong inhibitor of ER processing glucosidase I, a key cellular glycosidase involved in the elaboration of the glycan structure of glycoproteins.[11] In the search for a chemical chaperone therapy for Gaucher’s disease, Kelly et al. disclosed that the addition of subinhibitory concentrations (10 μm) of N-nonyl-1-deoxynojirimycin (NN-DNJ, 2) to a fibroblast culture medium leads to a …