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Review
. 2021 Oct 21:12:752117.
doi: 10.3389/fphys.2021.752117. eCollection 2021.

Human Sirtuin Regulators: The "Success" Stories

Alyson M Curry  1 , Dawanna S White  1 , Dickson Donu  1 , Yana Cen  1   2
Affiliations
Review

Human Sirtuin Regulators: The "Success" Stories

Alyson M Curry et al. Front Physiol. .

Abstract

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.

Keywords: activator; clinical trial; drug development; inhibitor; sirtuin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Structures of resveratrol and the SRT family of SIRT1 activators.
FIGURE 2
FIGURE 2
Summary of resveratrol clinical trial outcomes.
FIGURE 3
FIGURE 3
Chemical structures of EX-527 and CHIC-35.
FIGURE 4
FIGURE 4
Chemical structures of quercetin and its derivatives.
See this image and copyright information in PMC

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