Çok değerli C2-alkil trihidroksipiperidin mimarileri beta-glukoserebrosidaz aktivitesini modüle eder.

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Multivalent systems based on C2-alkylated (3R,4R,5R)-3,4,5-trihydroxypiperidines, members of the iminosugar family, were developed as modulators of the lysosomal enzyme β-glucocerebrosidase (GCase), whose deficiency causes Gaucher disease and is also related to Parkinson disease. The iminosugar units were successfully multimerized onto tri- and tetrapodal scaffolds and gold nanoparticles, enabling a systematic investigation of the multivalent effects. Both architectures exhibited a marked enhancement in inhibitory potency compared to a suitable monovalent reference compound, proving a strong multivalent effect. However, while tri- and tetravalent compounds primarily act as enzyme inhibitors in cellular assays, gold nanoparticle-based systems retain a productive chaperone window, promoting mutant N370S GCase rescue in Gaucher patient-derived fibroblasts by up to 1.7-fold at 100 nM, without detectable cytotoxicity. Overall, these findings highlight the critical role of scaffold organization in balancing enzyme inhibition and functional rescue in the design of multivalent pharmacological chaperones for Gaucher disease.

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