摘要
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.
The metabolic disorders of glycosphingolipid（GSL） are a relatively rare group of inherited diseases that have diverse and often neurodegenerative symptoms.And the lysosomal storage disorder is typical one of these diseases.It is caused by lysosomal storage of GSL substrates or several other glycoconjugates,due to deficiency in the activity of enzymes or protein factors involved in the degradation of glycosphingolipids in the lysosome.Now the main treatment strategy for these diseases is enzyme replacement therapy（ERT） which uses direct infusion of the recombinant enzyme into patients.However,the inherent defects of this strategy,for example,the recombinant enzymes cannot pass the blood-brain barrier,limit its application.So the second strategy called substrate reduction therapy（SRT）,which is involved in reducing the synthesis of glycosphingolipids to match the degradation activity of lysosome,is proposed.N-Alkylated iminosugars were thought to be used in SRT for its inhibition of the key enzyme,ceramide glucosyltransferase（CGT）,in GSL biosynthesis.Many iminosugars were designed and synthesized for improving their inhibitory potency,bioavailability,enzyme selectivity,and biological safety.After a successful clinical evaluation,one compound,namely N-butyldeoxynojirimycin（NB-DNJ）,has been used in the clinical treatment.On the other hand,iminosugars as chemical chaperones,can assist enzyme folding and stabilize the conformation of mutant enzymes to rescue their activity.This feature makes the pharmacological chaperone therapy（PCT） as an alternative novel therapeutic strategy for the treatment of lysosomal storage disorders.Given the ability of small molecules to be orally available,to penetrate the central nervous system（CNS）,and to have well-characterized pharmacological properties,the iminosugars are increasingly used in the treatment of lysosomal storage disorders,and would have a bright future.
出处
《中国科学：化学》
CAS
CSCD
北大核心
2012年第12期1732-1745,共14页
SCIENTIA SINICA Chimica
基金
国家自然科学基金项目(90713010
21072014)
国家重点基础研究发展计划(973计划
2012CB822100)资助
关键词
溶酶体蓄积症
氮杂糖
底物减少疗法
药理分子伴侣疗法
lysosomal storage disorders
iminosugars
substrate reduction therapy
pharmacological chaperone therapy
