Abstract
Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure–activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.
Highlights
Sirtuins are nicotinamide adenine dinucleotide (NAD+ )-dependent deacylases that catalyze the deacylation of histones and non-histone proteins with the transformation of NAD+ into nicotinamide and 2’-O-acyl-adenosine diphosphate (ADP)-ribose [1]
Compared with other that have a conserved compact acetyl substrate binding pocket, SIRT6 possesses a larger and wider sirtuins (SIRT1–5) that have a conserved compact acetyl substrate binding pocket, SIRT6 possesses a hydrophobic channel [30], which may contribute to the weak affinities and activities of the inhibitors larger and wider hydrophobic channel [30], which may contribute to the weak affinities and activities for SIRT6
We identified novel sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione by a fluorescent assay
Summary
Sirtuins are nicotinamide adenine dinucleotide (NAD+ )-dependent deacylases that catalyze the deacylation of histones and non-histone proteins with the transformation of NAD+ into nicotinamide and 2’-O-acyl-adenosine diphosphate (ADP)-ribose [1]. Molecules 2020, 25, x FOR PEER REVIEW have potential applications in the treatment of Huntington’s disease and cancers [11]. This has aroused the interest research groups around the world to develop sirtuin small molecule inhibitors. [18,19], and potent SIRT2 inhibitors and prevent the death of dopaminergic cells, hippocampal neurodegeneration, SirReal. SIRT1/2/3 inhibitor, which was discovered by screening the DNA encoded compound library [21,22]. Potent nanomolar SIRT1/2/3 inhibitor, which was discovered by screening the DNA encoded. Ex527, a SIRT1 inhibitor with IC50 of 60–100 nM, has been evaluated in clinical trials for the treatment compound library [21,22].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
