Glycogen Phosphorylase Inhibition in Metabolic Disorders

Glycogen phosphorylase is the rate-limiting enzyme in glycogenolysis, catalysing the release of glucose-1-phosphate from glycogen stores. Its dysregulation contributes to elevated hepatic glucose production in type 2 diabetes mellitus and supports aberrant metabolic programmes in certain cancers. Inhibition of this enzyme offers a dual therapeutic benefit: reducing hyperglycaemia by limiting hepatic glucose output and impairing tumour cell energy supply. Strategies have evolved from early active-site inhibitors to allosteric modulators and organ-selective prodrugs, guided by high-resolution crystal structures and computational design. Recent advances in assay standardisation, isoform selectivity and prodrug targeting have accelerated the translation of glycogen phosphorylase inhibitors towards clinical development, with global implications for metabolic health and oncology.

Research from Nature Portfolio

Recent work has focused on liver-targeted prodrugs of a validated glycogen phosphorylase inhibitor, employing a cholic acid conjugation strategy to enhance hepatic delivery and selectivity. One lead conjugate demonstrated improved metabolic stability, a marked increase in liver-to-plasma exposure ratio and a prolonged glucose-lowering effect in diabetic animal models. These findings underscore the promise of organ-selective prodrug design in refining pharmacokinetics, minimising off-target effects and achieving sustained therapeutic efficacy in metabolic disorders.

Glycogen Phosphorylase Inhibition in Metabolic Disorders publication trend

The graph below shows the total number of articles in glycogen phosphorylase inhibition in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Glycogen phosphorylase: Enzyme catalysing the phosphorolytic cleavage of glycogen to glucose-1-phosphate.

Glycogenolysis: Metabolic pathway of glycogen breakdown into glucose units.

Isoform: Variant form of an enzyme with distinct sequence and regulatory properties.

Allosteric site: Regulatory site on an enzyme distinct from the active site, modulating activity upon ligand binding.

IC50: Concentration of inhibitor required to reduce enzyme activity by 50 percent.

Ki: Equilibrium constant representing the affinity of an inhibitor for its target enzyme.

References

1. Multidisciplinary docking, kinetics and X-ray crystallography studies of baicalein acting as a glycogen phosphorylase inhibitor and determination of its’ potential against glioblastoma in cellular models. Chemico-Biological Interactions (2023).
2. Synthesis, In Silico and Kinetics Evaluation of N-(β-d-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(β-d-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as Glycogen Phosphorylase Inhibitors. International Journal of Molecular Sciences (2024).
3. Novel Liver-targeted conjugates of Glycogen Phosphorylase Inhibitor PSN-357 for the Treatment of Diabetes: Design, Synthesis, Pharmacokinetic and Pharmacological Evaluations. Scientific Reports (2017).
4. An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles. Nutrients (2022).
5. Optimization and Validation of an In Vitro Standardized Glycogen Phosphorylase Activity Assay. Molecules (2021).