中文摘要：

戈谢病（Gaucher disease,GD）是一种由于β-酸性葡萄糖脑苷脂酶（acidβ-glucocerebrosidase,GCase）基因突变引起的常染色体隐性遗传疾病,也是发病率最高的溶酶体贮积病。突变GCase的内质网关联降解和靶向溶酶体运转受阻是主要病因。酶替代疗法（enzyme replacement therapy,ERT）和底物降低疗法（substrate reduction therapy,SRT）是临床采用的主要治疗方法,但只对未涉及神经病变的Ⅰ型GD有效,且存在体内稳定性差和难以透过血脑屏障等弊端。GCase酶竞争性抑制剂可在低浓度底物的胞质中与突变酶结合,诱导酶折叠和运转;在高浓度底物的溶酶体中与酶解离,释放酶分子。因此,基于竞争性抑制剂的药物分子伴侣（pharmacological chaperone,PC）成为最具前景的药物。结合本课题组对GCase PC的研究,本文介绍了GCase的结构、催化机理及目前GCase PC的研究进展。重点讨论了脱氧野尻霉素类、环己亚胺醇类、C-糖苷衍生物、氨基环醇类和双环类PC的构效关系,简单介绍了其他非糖来源的PC,最后展望了GCase PC的前景,指出了今后研究中的发展方向。

英文摘要：

Gaucher disease（ GD） is a human autosomal recessive disorder mainly due to mutations in the gene encoding for the lysosomal enzyme acid β-glucocerebrosidase（ GCase）. It is the most common lysosomal storage disorder. Endoplasmic reticulum associated degradation（ ERAD） and limitation for translocation to lysosome are tw o main pathological factors for GD. So far,enzyme replcement therapy（ ERT） and substrate reduction therapy（ SRT） are approved medical treatments for type Ⅰ GD patients w ith non-neurological involvement. How ever,they are intrinsically associated w ith low stability in biological media as w ell as the impossibility to cross the blood brain barrier（ BBB）. GCase competitive inhibitors can bind mutant GCase in cytoplasm w ith low concentration substrates,induce it fold and translocate it to lysosome. In lysosome w ith high concentration substrates, competitive inhibitors dissociate from GCase and release it. Therefore, PCs（ pharmacological chaperones） based on competitive inhibitors become the most promising drugs. According to the research on GCase PC in our group,the structure and the catalytic mechanism of GCase and related GCase PCs are introduced. Particularly,the structure and activity relationships of deoxynojirimycin,1,5-dideoxy-1,5-imino-D-xylitol,isofagomine,aminoinositol and bicyclic iminosugar are discussed emphatically. In addition, other non-sugar derived PCs are briefly introduced. Finally,w e analysize the future prospect of GCase PCs and propose the directions in development.