Non-specific SIRT inhibition as a mechanism for the cytotoxicity of ginkgolic acids and urushiols

Ryckewaert, Lucie; Sacconnay, Lionel; Carrupt, Pierre‐Alain; Nurisso, Alessandra; Simões-Pires, Cláudia A.

doi:10.1016/j.toxlet.2014.07.002

Cited by 33 publications

(19 citation statements)

References 29 publications

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“…The antioxidative activity of GA has been reported to have multiple therapeutic effects including the treatment of cardiovascular disease, HIV infection, bacterial infections such as Escherichia coli and Staphylococcus aureus, and some tumors 7,8,19,20 . It has been suggested that GA may operate by several other pathways including: inhibition of fatty acid synthase 10 ; non-specific SIRT inhibition 11 ; activation of protein phosphatase type-2C 12 ; suppression of STAT3 activation through induction of PTEN and SHP-1 Tyrosine Phosphatase 21 , and protection against Aβ-induced synaptic dysfunction in the hippocampus 6 . www.nature.com/scientificreports www.nature.com/scientificreports/ In this study, we are the first to report the fusion inhibitory effect of GA on enveloped viruses representing the three classes of fusion proteins and the inhibition of a non-enveloped human adenovirus.…”

Section: Discussionmentioning

confidence: 99%

Ginkgolic acid inhibits fusion of enveloped viruses

Borenstein

Hanson

Markosyan

et al. 2020

Sci Rep

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Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-β (Aβ) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus.Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).Ginkgolic acids are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. Ginkgo biloba extracts (GBE) have been used as herbal supplements since at least the 16 th century and remain widely in use 1 . Major constituents of GBE include terpine trilactones (ginkgolide A, B, C, J, and bilobalide), flavonoid glycosides (quercetin and rutin), as well as Ginkgolic acids 2 . Ginkgolic acids are a mixture of several 2-hydroxy-6-alkylbenzoic acids in which the most common alkyl chains contain 13, 15, or 17 carbons. The 15 and 17 carbon chains are unsaturated at positions 8 and 10, respectively. The 3 Ginkgolic acid (GA) structures are, therefore, designated C13:0, C15:1, and C17:1 (Table S1) 3 .GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; potential rescue of amyloid-β (Aβ) induced synaptic impairment; and inhibition of HIV protease activity as well as HIV viral replication 4-7 . GA was also reported to have activity against Escherichia coli and Staphylococcus aureus 8 . Several ways in which GA works have been suggested including by SUMOylation inhibition activity; blocking formation of the E1-SUMO intermediate 9 ;...

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Section: Discussionmentioning

confidence: 99%

Ginkgolic acid inhibits fusion of enveloped viruses

Borenstein

Hanson

Markosyan

et al. 2020

Sci Rep

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“…This weaker inhibitory potential may be linked to solubility issues. We have previously demonstrated that the nonspecific SIRT inhibition by 6 induces higher cytotoxicity than the specific SIRT1 inhibition in HEK 293 and HeLa cells [21]. In this study, compounds 2 and 3 displayed a reduced viability of HEK 293 cells comparable to 6 at the tested concentrations ( Fig.…”

supporting

confidence: 53%

“…Crystallographic structures of the productive forms of human SIRT1 (PDB ID: 4I5I) and SIRT2 (PDB ID: 3ZGV) were retrieved from the Protein Data Bank (wwPDB; http://www.wwpdb.org/) [19,20]. The missing loop in SIRT2 was modelled according to our previously published protocol [21]. Both isoform structures were then prepared for structural inspection and docking in MOE 2012.10 by removing the crystallized water molecules and ligands, and by adding the missing hydrogen atoms.…”

Section: Protein and Ligand Structures Preparationmentioning

confidence: 99%

Alkaloids from Psychotria Target Sirtuins: In Silico and In Vitro Interaction Studies

et al. 2014

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Epigenetic enzymes such as histone deacetylases play a crucial role in the development of ageing-related diseases. Among the 18 histone deacetylase isoforms found in humans, class III histone deacetylases, also known as sirtuins, seem to be promising targets for treating neurodegenerative conditions. Recently, Psychotria alkaloids, mainly monoterpene indoles, have been reported for their inhibitory properties against central nervous system cholinesterase and monoamine oxidase proteins. Given the multifunctional profile of these alkaloids in the central nervous system, and the fact that the indole scaffold has been previously associated with sirtuin inhibition, we hypothesized that these indole derivatives could also interact with sirtuins. In the present study, alkaloids previously isolated from Psychotria spp. were evaluated for their potential interaction with human sirtuin 1 and sirtuin 2 by molecular docking and molecular dynamics simulation approaches. The in silico results allowed for the selection of five potentially active compounds, namely, prunifoleine, 14-oxoprunifoleine, E-vallesiachotamine, Z-vallesiachotamine, and vallesiachotamine lactone. The sirtuin inhibition of these compounds was confirmed in vitro in a dose-response manner, with preliminary information on their pharmacokinetics properties.

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“…41–43 Anacardic acid has recently been found to have potential to inhibit sirtuins. 44, 45 Inhibition by C646 has not been reported yet. Their inhibitory potency was evaluated by dose response experiments (Fig.…”

Section: Resultsmentioning

confidence: 95%

A label-free Sirtuin 1 assay based on droplet-electrospray ionization mass spectrometry

et al. 2016

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Sirtuin 1(SIRT1) is a NAD + -dependent deacetylase which has been implicated in age-related diseases such as cancer, Alzheimer's disease, type 2 diabetes, and vascular diseases. SIRT1 modulators are of interest for their potential therapeutic use and potential as chemical probes to study the role of SIRT1. Fluorescence-based assays used to identify SIRT1 activators have been shown to have artifacts related to the fluorophore substrates used in the assays. Such problems highlight the potential utility of a label-free high throughput screening (HTS) strategy. In this work, we describe a label-free SIRT1 assay suitable for HTS based on segmented flowelectrospray ionization-mass spectrometry (ESI-MS). In the assay, 0.5 μM SIRT1 was incubated with 20 μM acetylated 21-amino acid peptide, which acts as substrate for the protein. A stableisotope labeled product peptide was added to the assay mixture as an internal standard after reaction quenching. The resulting samples are formatted into 100 nL droplets segmented by perfluorodecalin and then infused at 0.8 samples/s into an ESI-MS. To enable direct ESI-MS analysis, 11 μM SIRT1 was dialyzed into a 200 μM ammonium formate (pH 8.0) buffer prior to use in the assay. This buffer was demonstrated to minimally affect enzyme kinetics and yet be compatible with ESI-MS. The assay conditions were optimized through enzyme kinetic study, and tested by screening an 80-compound library. The assay Z-factor was 0.7. Four inhibitors and no activators were detected from the library.

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Non-specific SIRT inhibition as a mechanism for the cytotoxicity of ginkgolic acids and urushiols

Cited by 33 publications

References 29 publications

Ginkgolic acid inhibits fusion of enveloped viruses

Ginkgolic acid inhibits fusion of enveloped viruses

Alkaloids from Psychotria Target Sirtuins: In Silico and In Vitro Interaction Studies

A label-free Sirtuin 1 assay based on droplet-electrospray ionization mass spectrometry

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