Celina Reverdy; Gaetan Gitton; Xiangying Guan; Indranil Adhya; Rama Dumpati; Samir Roy; Gauthier Errasti; Thomas Delacroix; Raj Chakrabarti
Bioorg. Med. Chem., 2022, 116999
https://doi.org/10.1016/j.bmc.2022.116999

Abstract

Among the sirtuin members, Sirt3 is one of the most important deacetylases as it regulates acetylation levels in mitochondria, which are linked to the metabolism of multiple organs and therefore involved in many types of human diseases such as age-related diseases, cancer, heart disease and metabolic diseases. In the current absence of any direct activator of Sirt3, the identification of new modulators could be a key step in the development of new therapeutics. Here we report the discovery of Sirt3 modulators thanks to DNA encoded library technology (ELT). The most enriched compounds after DEL selection against SIRT3 were evaluated according to their activity and affinity. Our best activator seems at least as potent as Honokiol (HKL) while the docking studies tend to show that our modulators probably interact with Sirt3 at an atypical site.