Cyclic peptide-based potent human SIRT6 inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Enzymology

Background:

• Sirtuin 6 (SIRT6) is a key enzyme involved in DNA repair and metabolic regulation.
• Dysregulation of SIRT6 activity is implicated in various diseases, highlighting its therapeutic potential.
• Developing specific inhibitors for SIRT6 is crucial for understanding its biological roles and for drug discovery.

Purpose of the Study:

• To discover and characterize novel inhibitors of human SIRT6.
• To evaluate the potency and selectivity of newly synthesized cyclic pentapeptides against SIRT6.
• To identify lead compounds for the development of targeted SIRT6-based therapies.

Main Methods:

• Synthesis of six novel side chain-to-side chain cyclic pentapeptides.
• In vitro enzymatic assays to measure inhibition of human SIRT6-catalyzed deacylation.
• Selectivity profiling against related sirtuin enzymes (SIRT1, SIRT2, SIRT3, SIRT5).

Main Results:

• All six cyclic pentapeptides demonstrated high potency (nanomolar range) as SIRT6 inhibitors.
• One compound exhibited significant selectivity for SIRT6 over SIRT2, SIRT3, and SIRT5.
• This lead compound showed a modest selectivity advantage for SIRT6 compared to SIRT1.

Conclusions:

• The synthesized cyclic pentapeptides are potent inhibitors of human SIRT6.
• The identified selective SIRT6 inhibitor represents a promising starting point for further drug development.
• These findings pave the way for the creation of more effective and targeted SIRT6-modulating therapeutics.