Small Changes Make the Difference for SIRT2: Two Different Binding Modes for 3-Arylmercapto-Acylated Lysine...

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Enzyme Inhibition

Background:

• Sirtuins (SIRTs) are a class of protein deacetylases crucial for regulating metabolism and stress responses.
• Dysregulation of sirtuins is linked to aging-related diseases, including cancer, making them attractive therapeutic targets.
• Development of selective sirtuin modulators is essential for chemical biology and drug discovery.

Purpose of the Study:

• To synthesize and characterize novel peptide derivatives as selective inhibitors of human sirtuins.
• To investigate the structure-activity relationships and binding modes of these inhibitors with Sirtuin 2 (SIRT2).

Main Methods:

• Synthesis of 3-aryl-mercapto-butyrylated peptide derivatives.
• Enzyme inhibition assays to determine inhibitory constants (K_D).
• Kinetic measurements, microscale thermophoresis (MST), and surface plasmon resonance (SPR) for binding analysis.

Main Results:

• 3-Aryl-mercapto-butyrylated peptide derivatives demonstrated potent and selective inhibition of Sirtuin 2 (SIRT2) with low nanomolar K_D values.
• Inhibitor binding involves the 3-aryl-mercapto moiety interacting with the SIRT2 selectivity pocket, inducing active site rearrangement.
• Alternative derivatives (3-aryl-mercapto-nonalyl or palmitoyl) exhibited a different binding mode, blocking both the hydrophobic channel and nicotinamide pocket.

Conclusions:

• Novel peptide derivatives represent effective and selective inhibitors of Sirtuin 2 (SIRT2).
• The findings provide insights into the molecular mechanisms of sirtuin inhibition and guide the design of future therapeutics.
• These selective SIRT2 inhibitors hold promise as chemical tools and potential therapeutic agents for diseases associated with sirtuin dysregulation.