Bivalent SIRT1 inhibitors.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Enzymology

Background:

• Sirtuins, particularly SIRT1, are crucial NAD+-dependent deacetylases involved in various (patho)physiological processes.
• Developing selective inhibitors for sirtuins is therapeutically important for numerous diseases.
• Monovalent inhibitors based on Nε-acetyl-lysine have shown potential but can lack selectivity.

Purpose of the Study:

• To design and synthesize novel bivalent compounds targeting SIRT1.
• To evaluate the inhibitory potencies and selectivity of these bivalent compounds against SIRT1 and related sirtuins (SIRT2, SIRT3).
• To establish a foundation for developing superior bivalent sirtuin inhibitors.

Main Methods:

• Synthesis of bivalent compounds (1-17) by linking lysine-based tripeptide scaffolds to functionalities via linkers.
• In vitro enzymatic assays to determine inhibitory potencies against SIRT1.
• Comparative analysis of inhibition and selectivity profiles against SIRT1, SIRT2, and SIRT3 for bivalent versus monovalent compounds.

Main Results:

• Several synthesized bivalent compounds exhibited stronger SIRT1 inhibition compared to monovalent counterparts (18, 19).
• Compound 6 demonstrated superior selectivity for SIRT1 over SIRT2 and SIRT3 compared to its monovalent analog (18).
• The bivalent strategy proved effective in enhancing both potency and selectivity.

Conclusions:

• Bivalent compounds offer an improved approach for SIRT1 inhibition.
• The developed bivalent inhibitors show enhanced potency and selectivity, outperforming monovalent analogs.
• This study provides a strong basis for the future design of advanced bivalent inhibitors targeting the sirtuin deacylase enzyme family.