Iminosugar based pharmacological chaperones: selecting new leads to target Gaucher, Morquio A and Hunter Disease

BACKGROUND: Pharmacological chaperone therapy (PCT) is emerging as a treatment for many lysosomal storage disorders. It offers several advantages, such as oral administration and reduced costs. PCs are able to recover endogenous enzyme activity and are thus the only treatment that targets the functional origin of LSDs at present. Unfortunately, a great hurdle is represented by the challenging identification of compounds which are suitable for use as chaperones, especially because the mechanisms behind these processes are still far from clear. The most promising PCs for LSDs reported to date are iminosugars, sugar mimetics with a nitrogen atom replacing the endocyclic oxygen of carbohydrates. METHODS: The inhibitory activity of a library of natural iminosugar analogues was initially assayed on a panel of 14 human lysosomal glycosidases and sulfatases, with the aim of identifying target enzyme(s) and the most promising molecules. On the basis of these findings, new properly functionalized compounds were designed and synthesized resulting in more potent inhibitors, suitable for testing as PCs in vivo. RESULTS: Among the screened glycosidases, glucocerebrosidase (GCase, the deficient enzyme in Gaucher disease) has proved to be the most affected. In particular, two piperidines functionalized in different positions with a lipophilic pendant were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts up to 1.5 fold. Moreover, sulfatase enzymes such as N-acetylgalactosamine-6-sulfatase (GALNS) and iduronate-2-sulfatase (IDS) were inhibited in the micromolar range bymultivalent compounds (obtained by grafting 9 bioactive units on the same scaffold). DISCUSSION: The close collaboration between synthetic chemists and molecular biologists allowed the identification of two new GCase PCs and two potent reversible inhibitors of GALNS and IDS, excellent candidates as PCs or enzyme stabilizers for Morquio A and Hunter syndrome.