Current Trends in Sirtuin Activator and Inhibitor Development

Abstract

Sirtuins are NAD+-dependent protein deacylases and key metabolic regulators, coupling the cellular energy state with selective lysine deacylation to regulate many downstream cellular processes. Humans encode seven sirtuin isoforms (Sirt1-7) with diverse subcellular localization and deacylase targets. Sirtuins are considered protective anti-aging proteins since increased sirtuin activity is canonically associated with lifespan extension and decreased activity with developing aging-related diseases. However, sirtuins can also assume detrimental cellular roles where increased activity contributes to pathophysiology. Modulation of sirtuin activity by activators and inhibitors thus holds substantial potential for defining the cellular roles of sirtuins in health and disease and developing therapeutics. Instead of being comprehensive, this review discusses the well-characterized sirtuin activators and inhibitors available to date, particularly those with demonstrated selectivity, potency, and cellular activity. This review also provides recommendations regarding the best-in-class sirtuin activators and inhibitors for practical research as sirtuin modulator discovery and refinement evolve.

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

“…Several efforts to develop SIRT activators or inhibitors have been managed by relying on natural products and related analogs, as well as via small molecule inhibitors or mechanism-based peptide modulators [148][149][150][151]. However, the structural similarity within SIRTs often complicates the rational design and development of selective ligands, especially for SIRT1-3.…”