Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-glucosidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease
Journal
Bioorganic & medicinal chemistry
Journal Volume
78
Date Issued
2022-12-12
Author(s)
Li, Huang-Yi
Chiu, Yu-Ting
Chang, Yu-Wen
Lin, Chu-Chung
Chou, Cheng-Li
Cheng, Wei-Chieh
Abstract
To discover small molecules as acid alpha-glucosidase (GAA) stabilizers for potential benefits of the exogenous enzyme treatment toward Pompe disease cells, we started from the initial screening of the unique chemical space, consisting of sixteen stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) to find out two primary stabilizers 17 and 18. Further external or internal structural modifications of 17 and 18 were performed to increase structural diversity, followed by the protein thermal shift study to evaluate the GAA stabilizing ability. Fortunately, pyrrolidine 21, possessing an l-arabino-typed configuration pattern, was identified as a specific potent rh-GAA stabilizer, enabling the suppression of rh-GAA protein denaturation. In a cell-based Pompe model, co-administration of 21 with rh-GAA protein significantly improved enzymatic activity (up to 5-fold) compared to administration of enzyme alone. Potentially, pyrrolidine 21 enables the direct increase of ERT (enzyme replacement therapy) efficacy in cellulo and in vivo.
Subjects
Acid alpha-glucosidase (GAA); Chemical space; Combinatorial chemistry; Cyclic nitrone; Iminosugar; Polyhydroxylated pyrrolidine; Pompe disease; Protein stabilizer; Protein thermal shift assay
SDGs
Type
journal article