Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors

Area of Science:

• Biochemistry
• Enzymology
• Medicinal Chemistry

Background:

• Retaining beta-glucosidases, including GBA, GBA2, and GBA3, play crucial roles in cellular processes.
• Cyclophellitol and its aziridine analogues are known mechanism-based inhibitors of beta-glucosidases.
• Understanding structure-activity relationships is key for developing targeted enzyme inhibitors.

Purpose of the Study:

• To evaluate the inhibitory potency of various cyclophellitol analogues against human GBA, GBA2, and GBA3.
• To compare the efficacy of N-alkyl, N-acyl, and N-sulfonyl cyclophellitol aziridine analogues.
• To inform the design of novel glycosidase probes with enhanced stability.

Main Methods:

• Synthesis and characterization of cyclophellitol aziridine analogues.
• Enzyme inhibition assays using purified human GBA, GBA2, and GBA3.
• Comparative analysis of inhibitory potency based on N-substituent variations.

Main Results:

• N-alkyl cyclophellitol aziridines exhibit potent inhibition against human retaining beta-glucosidases.
• Their inhibitory potency is comparable to N-acyl analogues.
• N-sulfonyl analogues demonstrate significantly weaker inhibitory activity.

Conclusions:

• The N-substituent critically influences the inhibitory potency of cyclophellitol aziridine analogues.
• N-alkyl aziridines represent promising scaffolds for developing effective beta-glucosidase inhibitors.
• These findings support the development of stable, activity-based glycosidase probes for therapeutic and research applications.