Ricerc@Sapienza

Introduction: In recent years, sirtuins (SIRTs) gained an increasing consideration because of their multiple key roles in several biological settings such as the regulation of transcription, energetic metabolism, cell cycle progression and cytodifferentiation, apoptosis, neuro- and cardio-protection, inflammation, cancer onset and progression. Since there is mounting evidence in favour of potential therapeutic applications of SIRT modulators in various age-related disorders, the search about them is quite active. Among the seven isoforms (SIRT1-7), the most well studied is certainly SIRT1, for which both activators and inhibitors are available, while for the others the development of specific modulators has just started.Areas covered: This review includes the patents regarding SIRT modulators released from 2015 to 2019 and provides a concise overview of the most relevant SIRT modulators developed so far.Expert opinion: Despite the knowledge about this family of broad-spectrum protein lysine deacylases has massively increased in the last few years, there are still many open questions, first of all, the exact mechanism of their involvement in various age-related conditions, including cancer. Most isoforms, in fact, can act either as tumour promoters or suppressors, depending on the specific tumour type, stage of development, microenvironment, and external stimuli. In the last few years, the debate about the mechanism of SIRT1 activation by some natural and synthetic compounds has been overcome in favour of a direct activation, and the first synthetic direct activators of SIRT6 have also been reported. Nevertheless, the search for isoform-specific SIRT activators as well as inhibitors is still at its infancy, a limited number of patents describing them has been released, and not many clinical trials are ongoing. However, it is extremely likely that the successes obtained in the structural elucidation and structure-based design approaches that very recently have led to potent and specific SIRT modulators will pave the way for the development of further modulators selective for every single isoform that could be useful both as tools to discriminate the functions of individual SIRTs in various biological contexts and as potential therapeutic agents.