Current Trends in Sirtuin Activator and Inhibitor Development

Bursch, Karina L.; Goetz, Christopher J.; Smith, Brian C.

doi:10.3390/molecules29051185

Cited by 5 publications

(1 citation statement)

References 241 publications

(609 reference statements)

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“…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.…”

Section: Future Perspectivesmentioning

confidence: 99%

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

Scarano,

Brullo,

Musumeci

et al. 2024

Pharmaceuticals

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Sirtuins (SIRTs) are classified as class III histone deacetylases (HDACs), a family of enzymes that catalyze the removal of acetyl groups from the ε-N-acetyl lysine residues of histone proteins, thus counteracting the activity performed by histone acetyltransferares (HATs). Based on their involvement in different biological pathways, ranging from transcription to metabolism and genome stability, SIRT dysregulation was investigated in many diseases, such as cancer, neurodegenerative disorders, diabetes, and cardiovascular and autoimmune diseases. The elucidation of a consistent number of SIRT–ligand complexes helped to steer the identification of novel and more selective modulators. Due to the high diversity and quantity of the structural data thus far available, we reviewed some of the different ligands and structure-based methods that have recently been used to identify new promising SIRT1/2 modulators. The present review is structured into two sections: the first includes a comprehensive perspective of the successful computational approaches related to the discovery of SIRT1/2 inhibitors (SIRTIs); the second section deals with the most interesting SIRTIs that have recently appeared in the literature (from 2017). The data reported here are collected from different databases (SciFinder, Web of Science, Scopus, Google Scholar, and PubMed) using “SIRT”, “sirtuin”, and “sirtuin inhibitors” as keywords.

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Section: Future Perspectivesmentioning

confidence: 99%

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

Scarano,

Brullo,

Musumeci

et al. 2024

Pharmaceuticals

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Comprehensive review of histone lactylation: Structure, function, and therapeutic targets

Xu,

Zhang,

Wang

et al. 2024

Biochemical Pharmacology

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Chemical synthesis of 2″OMeNAD+ and its deployment as an RNA 2′-phosphotransferase (Tpt1) ‘poison’ that traps the enzyme on its abortive RNA-2′-PO4-(ADP-2″OMe-ribose) reaction intermediate

Arnold,

Ghosh,

Kasprzyk

et al. 2024

Nucleic Acids Research

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RNA 2′-phosphotransferase Tpt1 catalyzes the removal of an internal RNA 2′-PO4 via a two-step mechanism in which: (i) the 2′-PO4 attacks NAD+ C1″ to form an RNA-2′-phospho-(ADP-ribose) intermediate and nicotinamide; and (ii) transesterification of the ADP-ribose O2″ to the RNA 2′-phosphodiester yields 2′-OH RNA and ADP-ribose-1″,2″-cyclic phosphate. Although Tpt1 enzymes are prevalent in bacteria, archaea, and eukarya, Tpt1 is uniquely essential in fungi and plants, where it erases the 2′-PO4 mark installed by tRNA ligases during tRNA splicing. To identify a Tpt1 ‘poison’ that arrests the reaction after step 1, we developed a chemical synthesis of 2″OMeNAD+, an analog that cannot, in principle, support step 2 transesterification. We report that 2″OMeNAD+ is an effective step 1 substrate for Runella slithyformis Tpt1 (RslTpt1) in a reaction that generates the normally undetectable RNA-2′-phospho-(ADP-ribose) intermediate in amounts stoichiometric to Tpt1. EMSA assays demonstrate that RslTpt1 remains trapped in a stable complex with the abortive RNA-2′-phospho-(ADP-2″OMe-ribose) intermediate. Although 2″OMeNAD+ establishes the feasibility of poisoning and trapping a Tpt1 enzyme, its application is limited insofar as Tpt1 enzymes from fungal pathogens are unable to utilize this analog for step 1 catalysis. Analogs with smaller 2″-substitutions may prove advantageous in targeting the fungal enzymes.

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Current Trends in Sirtuin Activator and Inhibitor Development

Cited by 5 publications

References 241 publications

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

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

Comprehensive review of histone lactylation: Structure, function, and therapeutic targets

Chemical synthesis of 2″OMeNAD+ and its deployment as an RNA 2′-phosphotransferase (Tpt1) ‘poison’ that traps the enzyme on its abortive RNA-2′-PO4-(ADP-2″OMe-ribose) reaction intermediate

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