Polyhydroxylated pyrrolidines may increase the efficacy of enzyme replacement therapy (ERT) efficacy in patients with Pompe disease (PD), according to a recent study published in Bioorganic & Medicinal Chemistry.

“It is the first report to describe how to initially use the in-house 2-aminomethyl polyhydroxylated pyrrolidines -based iminosugar collection (16 members) in the GAA protein stability study via the protein thermal shift evaluation system,” the authors wrote.

This experimental study first assessed the unique chemical space, identifying 16 stereoisomers of 2-aminomethyl polyhydroxylated pyrrolidines (ADMDPs) and 2 main stabilizers, referred to as 17 and 18. Afterward, the researchers achieved structural diversity by inducing modifications to such molecules. They confirmed their stabilizing ability through a protein thermal shift study.

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Likewise, pyrrolidine 21 showcased potent stabilizing activity for the recombinant human alpha-glucosidase (rh-GAA) by preventing protein degradation, possibly due to its L-arabino type of structure. Interestingly, administering rh-GAA in association with pyrrolidine 21 led to a marked improvement in enzymatic activity by up to 5 fold after 72 hours from the administration compared to rh-GAA alone.

The researchers observed these findings first in an in vivo model and could reproduce similar results in vivo in GAA knockout mice. Only the pyrrolidine 21 dosage of 200 mg per kg achieved this effect, whereas 100 mg per kg was not as successful.

Moreover, the enzymatic activity increased 2.8-fold in the gastrocnemius muscle, where ERT has been shown to be less efficient. The cardiac tissue exhibited a 1.3-fold enzyme activity increase. This finding further suggests a dose-response relation between the stabilizers and enzyme activity.

“Finally, our exciting results demonstrate that not only the co-treatment of pyrrolidine 21 with rh-GAA will be a potential benefit for Pompe disease treatment, but also this unique chemical space (16 members) can be extensively applied to discover new protein stabilizers for other protein drugs to improve the efficacy of enzyme replacement therapy (ERT),” the authors concluded.


Yi H, Chung N, Wen Y. et al. Harnessing polyhydroxylated pyrrolidines as a stabilizer of acid alpha-gluco‐sidase (GAA) to enhance the efficacy of enzyme replacement therapy in Pompe disease. Bioorg Med Chem. Published online December 7, 2022. doi:10.1016/j.bmc.2022.117129