Development of Tunable Mechanism-Based Carbasugar Ligands that Stabilize Glycoside Hydrolases through the Formation of Transient Covalent Intermediates.

ABSTRACT: Mutations in many members of the set of human lysosomal glycoside hydrolases cause a wide range of lysosomal storage diseases. As a result, much effort has been directed toward identifying pharmacological chaperones of these lysosomal enzymes. The majority of the candidate chaperones are active site-directed competitive iminosugar inhibitors but these have met with limited success. As a first step toward an alternative class of pharmacological chaperones we explored the potential of small molecule mechanism-based reversible covalent inhibitors to form transient enzyme-inhibitor adducts. By serial synthesis and kinetic analysis of candidate molecules, we show that rational tuning of the chemical reactivity of glucose-configured carbasugars delivers cyclohexenyl-based allylic carbasugar that

SUBMITTER: Bhosale S 

PROVIDER: S-EPMC11459473 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature