The human sirtuins are a group of NAD+-dependent protein deacylases. They “erase” acyl modifications from lysine residues in various cellular targets including histones, transcription factors, and metabolic enzymes. Through these far-reaching activities, sirtuins regulate a diverse array of biological processes ranging from gene transcription to energy metabolism. Human sirtuins have been intensely pursued by both academia and industry as therapeutic targets for a broad spectrum of diseases such as cancer, neurodegenerative diseases, and metabolic disorders. The last two decades have witnessed a flood of small molecule sirtuin regulators. However, there remain relatively few compounds targeting human sirtuins in clinical development. This reflects the inherent issues concerning the development of isoform-selective and potent molecules with good drug-like properties. In this article, small molecule sirtuin regulators that have advanced into clinical trials will be discussed in details as “successful” examples for future drug development. Special attention is given to the discovery of these compounds, the mechanism of action, pharmacokinetics analysis, formulation, as well as the clinical outcomes observed in the trials.
Among all the NAD+ precursors, nicotinamide riboside (NR) has gained the most attention as a potent NAD+-enhancement agent. This recently discovered vitamin, B3, has demonstrated excellent safety and efficacy profiles and is orally bioavailable in humans. Boosting intracellular NAD+ concentrations using NR has been shown to provide protective effects against a broad spectrum of pathological conditions, such as neurodegenerative diseases, diabetes, and hearing loss. In this review, an integrated overview of NR research will be presented. The role NR plays in the NAD+ biosynthetic pathway will be introduced, followed by a discussion on the synthesis of NR using chemical and enzymatic approaches. NR’s effects on regulating normal physiology and pathophysiology will also be presented, focusing on the studies published in the last five years.
Human sirtuins play important roles in various cellular events including DNA repair, gene silencing, mitochondrial biogenesis, insulin secretion and apoptosis. They regulate a wide array of protein and enzyme targets through their NAD+‐dependent deacetylase activities. Sirtuins are also thought to mediate the beneficial effects of low‐calorie intake to extend longevity in diverse organisms from yeast to mammals. Small molecules mimicking calorie restriction to stimulate sirtuin activity are attractive therapeutics against age‐related disorders such as cardiovascular diseases, diabetes and neurodegeneration. Little is known about one of the mitochondrial sirtuins, SIRT5. SIRT5 has emerged as a critical player in maintaining cardiac health and neuronal viability upon stress and functions as a tumour suppressor in a context‐specific manner. Much has been debated about whether SIRT5 has evolved away from being a deacetylase because of its weak catalytic activity, especially in the in vitro testing. We have, for the first time, identified a SIRT5‐selective allosteric activator, nicotinamide riboside (NR). It can increase SIRT5 catalytic efficiency with different synthetic peptide substrates. The mechanism of action was further explored using a combination of molecular biology and biochemical strategies. Based on the existing structural biology information, the NR binding site was also mapped out. These activators are powerful chemical probes for the elucidation of cellular regulations and biological functions of SIRT5. The knowledge gained in this study can be used to guide the design and synthesis of more potent, isotype‐selective SIRT5 activators and to develop them into therapeutics for metabolic disorders and age‐related diseases.
Multifunctional activity-based chemical probes enable sirtuin labeling, affinity capture, PROTAC construction, and inhibitor discovery.
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