高雪氏症是溶小體堆積症中最普遍的疾病，其原因主要是由於溶小體內之葡萄醣腦苷脂酵素之活性不足，進而造成神經鞘脂中之葡萄醣腦苷脂堆積在溶小體內。N-nonyl-deoxynojirimycin (NN-DNJ)為目前科學界公認之參考助疊小分子，其可在次抑制濃度 (subinhibitory concentration)提升特定突變葡萄醣腦苷脂酵素 (N370S)之活性，但其也會抑制溶小體內α-glucosidase之活性進而造成細胞產生副作用。因此我們不但希望發展能夠提升突變酵素活性外，也希望能減少抑制溶小體內α-glucosidase之化學助疊小分子，藉由組合式化學的方式我們以NN-DNJ為參考分子，合成一系列經由多元修飾疏水性基團的亞胺醣衍生物小分子，並同時利用酵素抑制活性檢測出亞胺醣衍生物60, 62與67其皆為相當有效之抑制劑。另外酵素抑制檢測及利用電腦軟體進行配體嵌合預測指出小分子疏水性官能基的部分與抑制酵素的能力皆有一定程度的關聯性。
亞胺醣衍生物62與67可提升高雪氏症細胞內突變酵素之活性，此外我們再將此助疊小分子62與 67，將其亞胺醣的部分進行多元修飾與其他五環亞胺醣鍵結並保留其疏水性基團，合成出之新穎分子經由細胞生物檢測發現，亞胺醣衍生物69與73不但能提升高雪氏症細胞內突變酵素之活性亦不會抑制溶小體內α-glucosidase之活性，為相當具潛力之助疊小分子。

Gaucher disease is one of the most prevalent lysosomal storage diseases caused by deficient lysosomal β-glucocerebrosidase (Gcase) activity, which leads to accumulation of the sphingolipid glucoslceramide in the lysosomes. NN-DNJ has been discovered as a chemical chaperone. It raises the folded population of the mutant enzyme (N370S) at subinhibitory concentration. However, it also inhibits the lysosomal α-glucosidase activity which causes some side effects. Therefore, we hope to develop new chemical chaperones not only for potency but also for enzyme selectivity. The lipophilic group of NN-DNJ was modified to a series of derivatives by using combinatorial approach. The results of the enzyme activity evaluation showed that DNJ-based six-membered derivatives 60, 62 and 67 are potent Gcase inhibitors. The preliminary SAR study and computational docking models indicated a correlation between lipophilicity and enzyme inhibiton.
In our cell-based study (N370S), compounds 62 and 67 showed potent chemical chaperone effects. In addition, we kept the hydrophobic moieties from 62 and 67 and modified the six-membered iminosugar moiety to new five-membered ones, which have not been studied before. Interestingly, several new molecules such as 69 and 73 showed potent chemical chaperone effects and importantly no side effects observed.

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