Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 2

Review
In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010.
[updated ].

Excerpt

Type Ia Congenital Disorders of Glycosylation (CDG-Ia) is the most common form of the Congenital Disorders of Glycosylation. This autosomal recessive disorder impairs the synthesis of N-linked oligosaccharide chains and is caused by defects in the PMM2 gene. PMM2 encodes phosphomannomutase 2, which is responsible for the conversion of mannose-6-P [Man-6-P] to Man-1-P. Currently, there is no treatment for CDG-Ia patients. The current project aimed to identify novel non-competitive inhibitors of phosphomannose isomerase, PMI. as potential therapeutic treatments for these patients. The developed probe ML096 (CID-25199533) inhibits human PMI and may inhibit other PMI orthologs due to the highly conserved nature of the enzyme. The probe is membrane permeable and, as a result can also be used to inhibit PMI in living cells. Thus, the probe may serve as a therapeutic treatment for CDG-Ia patients by blocking the catabolism of Man-6-P in cells, thereby redirecting it towards protein glycosylation using this residual PMM2 activity.

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