Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity

Area of Science:

• Biochemistry
• Mitochondrial Biology
• Drug Discovery

Background:

• Sirtuins are NAD+-dependent protein lysine deacylases involved in aging and related diseases.
• Mammalian Sirtuin 4 (Sirt4), located in mitochondria, is a potential therapeutic target for cancer and metabolic disorders.
• Currently, no potent and selective Sirt4 inhibitors are available.

Purpose of the Study:

• To identify and characterize potent and selective small-molecule inhibitors of Sirtuin 4 (Sirt4).
• To provide novel chemical tools for investigating Sirt4's role in cellular processes and disease.
• To establish lead compounds for the development of Sirt4-specific therapeutics.

Main Methods:

• Target-based virtual screening to identify initial hit compounds.
• Focused screening and structure-assisted design to optimize lead compounds.
• Kinetic analyses, docking models, and cellular assays to characterize inhibitor activity and selectivity.

Main Results:

• Identification of four first-in-class potent Sirt4 inhibitors.
• Kinetic data suggests compounds compete with the acyl peptide substrate at Sirt4's unique binding site.
• One compound (69) demonstrated high isoform selectivity and cellular activity.
• Compounds showed preference for Sirt4 over other sirtuin isoforms.

Conclusions:

• The study presents the first potent and selective small-molecule inhibitors of Sirt4.
• These inhibitors provide valuable tools for understanding Sirt4 function and its role in disease.
• The identified compounds serve as promising lead structures for further optimization into therapeutic agents.