论文部分内容阅读
鞘糖脂代谢异常是一类罕见的遗传性疾病,这类疾病种类繁多,通常具有神经病变症状.其中溶酶体蓄积症是这类疾病中较为典型的一类,由溶酶体内参与鞘糖脂降解的酶或蛋白因子活性缺失导致代谢底物或者一些糖缀合物蓄积溶酶体内而引起.目前这类疾病的主要治疗策略是酶替代疗法(ERT),即为病人补充缺失的酶,但这种策略固有的缺陷如重组酶无法通过血脑屏障等限制了其运用.针对这种情况,底物减少疗法(SRT)这种旨在减少鞘糖脂合成来匹配溶酶体降解能力的新型治疗策略被提了出来.N-烷基化氮杂糖因为能够抑制鞘糖脂合成过程中的关键酶—葡萄糖神经酰胺转移酶(CGT)被认为可以用于SRT.各种氮杂糖被设计合成以改善其抑制活性、选择性、生物利用度、生物安全性等特性.其中NB-DNJ通过了临床试验,已成功用于临床治疗.氮杂糖的另一个特性是作为分子伴侣能够辅助突变酶正确折叠并稳定其构象使酶恢复活性,这使得药理分子伴侣疗法(PCT)成为治疗溶酶体蓄积症的新型治疗策略.氮杂糖具有小分子药物口服利用度高、中枢神经系统渗透性强、生物及药理特性明显等优点,其用于治疗溶酶体蓄积症的临床试验不断增加,在治疗溶酶体蓄积症方面明显的应用前景光明.
Glycosphingolipids metabolic abnormalities is a rare class of genetic diseases, a wide range of these diseases, usually with neuropathy symptoms, of which lysosomal storage disease is more typical of this type of disease, by the lysosomal participation of sphingosine Lack of lipase-degrading enzyme or protein factor leads to the accumulation of lysosomal substrates or some glycoconjugates, and the major treatment strategy for these diseases today is enzyme replacement therapy (ERT), which is to replenish patients with missing enzymes, However, the inherent drawbacks of this strategy, such as the inability of recombinases to cross the blood-brain barrier, limit their use.In response, substrate reduction therapy (SRT), aiming to reduce glycosphingolipid synthesis to match lysosomal degradation A new therapeutic strategy has been proposed: N-alkylated azasugar is believed to be useful for SRT because of its ability to inhibit the key enzyme in glycosphingolipid synthesis - glucosylceramide transferase (CGT) Design and synthesis to improve its inhibitory activity, selectivity, bioavailability, biosafety and other characteristics of which NB-DNJ passed the clinical trials, has been successfully used in clinical treatment. Another characteristic of azaserose as a molecular chaperone energy Enzyme-chaperone therapy (PCT) has become a new therapeutic strategy for the treatment of lysosomal storage disease because of its ability to properly fold and stabilize the conformation of the mutant enzyme and stabilize its conformation. Azaseride has the advantages of oral administration of small molecule drugs, Systematic permeability, obvious biological and pharmacological properties, etc. Its clinical trial for the treatment of lysosomal storage diseases has been continuously increasing. It has a bright prospect in the treatment of lysosomal accumulation diseases.