The Current State of NAD⁺‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets

Abstract

Abstract:Sirtuins are NAD + -dependent protein deacylases that cleave off acetyl, as well as other acyl groups, from the ε-amino group of lysines in histones and other substrate proteins. Seven sirtuin isotypes (Sirt1-7) have been identified in mammalian cells. As sirtuins are involved in the regulation of various physiological processes such as cell survival, cell cycle progression, apoptosis, DNA repair, cell metabolism, and caloric restriction, a dysregulation of their enzymatic activity has been associated with the pathogenesis of neoplastic, metabolic, infectious, and neurodegenerative diseases. Thus, sirtuins are promising targets for pharmaceutical intervention. Growing interest in a modulation of sirtuin activity has prompted the discovery of several small molecules, able to inhibit or activate certain sirtuin isotypes. Herein, we give an update to our previous review on the topic in this journal , focusing on recent developments in sirtuin biology, sirtuin modulators, and their potential as novel therapeutic agents.

Validation of the Slow Off‐Kinetics of Sirtuin‐Rearranging Ligands (SirReals) by Means of Label‐Free Electrically Switchable Nanolever Technology

“…However, for some disease scenarios, including Huntington's disease and some cancer types, it has not yet been finally clarified whether Sirt2 has to be up‐ or downregulated or even inhibited to ameliorate specific disease conditions. The urgent need for suitable tool compounds to further investigate the cellular effects of Sirt2 deacetylation and validate Sirt2 as a drug target led to the discovery of a number of drug‐like Sirt2‐selective small‐molecule inhibitors, which have been reviewed elsewhere …”

Targeting anti‐aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis

“…The sirtuin family consists of seven members, sirtuin 1, sirtuin 2, sirtuin 3, sirtuin 4, sirtuin 5, sirtuin 6, and sirtuin 7, in mammals. All the seven members possess distinct activity, target, and tissue specificity but have a common NAD+ binding site . There are four classified groups of Sirtuins: group I, to which Sirt1‐Sirt3 belongs; group II, to which Sirt4 belongs; group III, which comprises of Sirt5; and group IV, to which Sirt6 and Sirt7 belong.…”

“…All the seven members possess distinct activity, target, and tissue specificity but have a common NAD+ binding site. [20][21][22]24,36 There are four classified groups of Sirtuins: group I, to which Sirt1-Sirt3 belongs; group II, to which Sirt4 belongs; group III, which comprises of Sirt5; and group IV, to which Sirt6 and Sirt7 belong. Different members of the Sirtuin family possess different localizations ( Figure 1).…”

Total Synthesis of Altissimacoumarin D, a Small Molecule Sirtuin1 Activator

“…The seven human sirtuins, Sirt1-7, are implicated in a number of disease conditions and there is much interest in both activators and inhibitors of sirtuin enzymes. 15 Although some dietary natural products such as resveratrol, quercetin or epigallocatechin gallate are reported as sirtuin modulators, their promiscuous nature is non-ideal for use as chemical probes and more selective molecules are needed. A recent lead from natural product screening comes from Ailanthus altissima (the tree of heaven), a plant used in Chinese and Korean traditional medicine.…”