Multivalent Calixarene-Iminosugar Conjugates as Pharmacological Chaperones for β-Glucocerebrosidase Reactivation
Multivalent Calixarene-Iminosugar Conjugates as Pharmacological Chaperones for β-Glucocerebrosidase Reactivation
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Original abstract
Reduced β-glucocerebrosidase (GCase) activity is the molecular hallmark of Gaucher disease and the major genetic risk factor for Parkinson's disease. Pharmacological chaperones (PCs), which stabilize mutant GCase and restore its lysosomal trafficking, represent a promising therapeutic strategy, although no GCase PC is currently available in clinical practice. To investigate the impact of multivalency and molecular architecture on GCase modulation, we designed and synthesized a series of calix[4]arene-based multivalent trihydroxypiperidine conjugates differing in valency and in the presentation of the pharmacophore at the upper or lower rim of the macrocycle, together with appropriate monovalent reference compounds. All multivalent derivatives exhibited low-micromolar GCase inhibition and a pronounced multivalent effect. Comparison with monovalent reference compounds identified the N-alkylated trihydroxypiperidine as the essential pharmacophore and revealed a complementary contribution of the calixarene scaffold to GCase inhibition. More importantly, compounds 1, 3 and 4 significantly restored GCase activity in N370S Gaucher fibroblasts, with tetravalent derivatives 3 and 4 remaining active at 1 μM, a ten-fold lower concentration than our previously reported trihydroxypiperidine monovalent PC. Furthermore, compound 3 also reduced intracellular reactive oxygen species, highlighting calix[4]arene-based multivalency as a promising strategy for the development of multifunctional GCase-targeted therapeutics.