New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies

Deng, Jieying; Liu, Zemin; Zhu, Kai-Rong; Cui, Guiling; Liu, Linxia; Yan, Yu‐Hang; Ning, Xiang-Li; Yu, Zeping; Li, Guobo; Qi, Qingrong

doi:10.1016/j.bioorg.2023.106487

Cited by 2 publications

(2 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to prior studies with thioacetyl peptide inhibitors [ 178 , 180 ], shortening the length of TS peptides did not improve potency towards Sirt5 [ 197 ]. Thioglutaryl pseudopeptides have also been developed as alternative Sirt5 inhibitors with IC 50 values of 120–730 nM and ~240–5000-fold selectivity for Sirt5 over Sirt1/2/3/6 [ 224 ].…”

Section: Mechanism-based Sirtuin Inhibitorsmentioning

confidence: 99%

Current Trends in Sirtuin Activator and Inhibitor Development

Bursch,

Goetz,

Smith

2024

Molecules

View full text Add to dashboard Cite

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.

show abstract

Section: Mechanism-based Sirtuin Inhibitorsmentioning

confidence: 99%

Current Trends in Sirtuin Activator and Inhibitor Development

Bursch,

Goetz,

Smith

2024

Molecules

View full text Add to dashboard Cite

show abstract

“…As SIRT5 inhibitors, novel ε-N-thioglutaryl-lysine derivatives shown strong inhibitory effects on SIRT5 (Deng et al, 2023). The difficulty may therefore lie rather in converting experimental findings into therapeutic formulations.…”

Section: Quercetin Inhibits Necroptosis In Cardiomyocytes By Regulati...mentioning

confidence: 99%

Quercetin inhibits necroptosis in cardiomyocytes after ischemia–reperfusion via DNA‐PKcs‐SIRT5‐orchestrated mitochondrial quality control

Chang,

Zhang,

Huang

et al. 2024

Phytotherapy Research

View full text Add to dashboard Cite

We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia–reperfusion stress. An enzyme‐linked immunosorbent assay was employed in the in vivo experiments to assess myocardial injury markers, measure the transcript levels of SIRT5/DNAPK‐cs/MLKL during various time intervals of ischemia–reperfusion, and observe structural changes in cardiomyocytes using transmission electron microscopy. In in vitro investigations, adenovirus transfection was employed to establish a gene‐modified model of DNA‐PKcs, and primary cardiomyocytes were obtained from a mouse model with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC‐1 fluorescence assay, Seahorse energy analysis, and various other assays were applied to corroborate the regulatory influence of quercetin on the MQC network in cardiomyocytes after ischemia–reperfusion. In vitro experiments demonstrated that ischemia–reperfusion injury caused changes in the structure of the myocardium. It was seen that quercetin had a beneficial effect on the myocardial tissue, providing protection. As the ischemia–reperfusion process continued, the levels of DNA‐PKcs/SIRT5/MLKL transcripts were also found to change. In vitro investigations revealed that quercetin mitigated cardiomyocyte injury caused by mitochondrial oxidative stress through DNA‐PKcs, and regulated mitophagy and mitochondrial kinetics to sustain optimal mitochondrial energy metabolism levels. Quercetin, through SIRT5 desuccinylation, modulated the stability of DNA‐PKcs, and together they regulated the “mitophagy‐unfolded protein response.” This preserved the integrity of mitochondrial membrane and genome, mitochondrial dynamics, and mitochondrial energy metabolism. Quercetin may operate synergistically to oversee the regulation of mitophagy and the unfolded protein response through DNA‐PKcs‐SIRT5 interaction.

show abstract

New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies

Cited by 2 publications

References 40 publications

Current Trends in Sirtuin Activator and Inhibitor Development

Current Trends in Sirtuin Activator and Inhibitor Development

Quercetin inhibits necroptosis in cardiomyocytes after ischemia–reperfusion via DNA‐PKcs‐SIRT5‐orchestrated mitochondrial quality control

Contact Info

Product

Resources

About