268. Discovery of novel compounds as potent activators of Sirt3

CĂ©lina Reverdy, Gaetan Gitton, Xiangying Guan, Indranil Adhya, Rama Krishna Dumpati, Samir Roy, Santu Chall, Gauthier Errasti, Thomas Delacroix and Raj Chakrabarti; bioRxiv; (2022); DOI: 10.1101/2022.01.05.475007 (open access)

Among the sirtuin enzymes, 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 age-related human diseases such as cancer, heart diseases and metabolic diseases. Given the dearth of direct activators 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, including activators, through the use of DNA encoded library technology (DEL). 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 suggest that our modulators interact with Sirt3 at an atypical site. Our results establish the attractiveness of the DEL technology in identifying novel and potent Sirt3 activators and, therefore, in associated therapeutic applications.