Sirtuin Inhibition: Strategies, Inhibitors, and Therapeutic Potential

Sirtuins have been increasingly demonstrated to be able to catalyze the removal of an ever-expanding list of acyl groups from Nε-acyl-lysines. Sirtuin-catalyzed deacylation has an important regulatory role in vital cellular processes, such as DNA repair and metabolism. Recent structural and/or biochemical studies have enriched our mechanistic understanding of the sirtuin-catalyzed deacylation reaction. Several highly potent and/or selective inhibitors against the sirtuin-catalyzed deacylation reaction have been identified via catalytic mechanism-based design and chemical library screening. Recent pharmacological studies with sirtuin inhibitors have helped present a stronger case for sirtuin inhibition as a novel therapy for human disease, such as cancer and neurodegeneration. The β-NAD+-dependent Nε-acyl-lysine deacylation reaction catalyzed by sirtuin family members has been increasingly demonstrated to be important in regulating multiple crucial cellular processes and has also been proposed to be a therapeutic target for multiple human diseases. Accordingly, its inhibitors have been actively pursued over the past few years. In addition, we have also seen the pharmacological assessment of sirtuin inhibitory compounds, although to a lesser extent. In this review, we first discuss how sirtuin inhibitors were discovered with the use of various approaches. We then follow with a discussion of pharmacological studies using sirtuin inhibitors. Our aim here is to set a stage for developing future superior sirtuin inhibitors and for an expanded effort in exploiting inhibitors to explore and/or validate the therapeutic potential stemming from the inhibition of the sirtuin-catalyzed deacylation reaction. The β-NAD+-dependent Nε-acyl-lysine deacylation reaction catalyzed by sirtuin family members has been increasingly demonstrated to be important in regulating multiple crucial cellular processes and has also been proposed to be a therapeutic target for multiple human diseases. Accordingly, its inhibitors have been actively pursued over the past few years. In addition, we have also seen the pharmacological assessment of sirtuin inhibitory compounds, although to a lesser extent. In this review, we first discuss how sirtuin inhibitors were discovered with the use of various approaches. We then follow with a discussion of pharmacological studies using sirtuin inhibitors. Our aim here is to set a stage for developing future superior sirtuin inhibitors and for an expanded effort in exploiting inhibitors to explore and/or validate the therapeutic potential stemming from the inhibition of the sirtuin-catalyzed deacylation reaction.