Phosphomannomutase-2 (PMM2) deficiency leads to the prominent Congenital Disorder of Glycosylation (CDG), a rare disease currently lacking effective treatment options. The complete absence of PMM2 activity is incompatible with life, and all patients carry at least one missense destabilising variant that allows residual enzymatic function. This makes PMM2-CDG amenable to pharmacological chaperone treatment. Glucose-1,6-bisphosphate (Glc-1,6-P2) is PMM2's natural activator and stabiliser, but its clinical application is severely limited due to its unfavourable physicochemical profile. Here, we applied the bioprecursor prodrug strategy to design and synthesise Lipo-Glc-1,6-P2, a novel prodrug with good stability and oral bioavailability. Its advantageous physicochemical profile was confirmed through metabolomics-based studies in fibroblasts derived from PMM2-CDG patient.
Lipo‐Glc‐1,6‐P2: A Bioprecursor Prodrug for Phosphomannomutase‐2 Congenital Disorder of Glycosylation
Bruno Hay Mele;
2026-01-01
Abstract
Phosphomannomutase-2 (PMM2) deficiency leads to the prominent Congenital Disorder of Glycosylation (CDG), a rare disease currently lacking effective treatment options. The complete absence of PMM2 activity is incompatible with life, and all patients carry at least one missense destabilising variant that allows residual enzymatic function. This makes PMM2-CDG amenable to pharmacological chaperone treatment. Glucose-1,6-bisphosphate (Glc-1,6-P2) is PMM2's natural activator and stabiliser, but its clinical application is severely limited due to its unfavourable physicochemical profile. Here, we applied the bioprecursor prodrug strategy to design and synthesise Lipo-Glc-1,6-P2, a novel prodrug with good stability and oral bioavailability. Its advantageous physicochemical profile was confirmed through metabolomics-based studies in fibroblasts derived from PMM2-CDG patient.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
