The polyanions heparin and suramin impede binding of free adenine to a DNA glycosylase from C. pseudotuberculosis

Eberle, Raphael J.; Coronado, Mônika A.; Peinado, Rafaela dos S.; Moraes, Fábio Rogério de; Olivier, Danilo S.; Dreyer, Thiago R.; Lopes, Débora de Oliveira; Luz, Brenda Silva Rosa da; Azevedo, Vasco; Arni, Raghuvir K.

doi:10.1016/j.ijbiomac.2018.12.067

Cited by 5 publications

(7 citation statements)

References 51 publications

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“… 40 ). Interestingly, defibrotide (oligonucleotides) and heparins (proteoglycans) share similarities in charge distributions and binding patterns ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Shi¹,

Gandhi²,

Smith³

et al. 2021

JCI Insight

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Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET-and histone-accelerated disease states.

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“… 40 ). Interestingly, defibrotide (oligonucleotides) and heparins (proteoglycans) share similarities in charge distributions and binding patterns ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Shi¹,

Gandhi²,

Smith³

et al. 2021

JCI Insight

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show abstract

“…In previous work, defibrotide's polyanionic properties have been shown to include binding with high affinity to specific heparin-binding proteins including basic fibroblast growth factor (bFGF) (40). Interestingly, defibrotide (oligonucleotides) and heparins (proteoglycans) share similarities in charge distributions and binding patterns (58).…”

Section: Discussionmentioning

confidence: 99%

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Shi

Gandhi

Smith

et al. 2021

Preprint

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Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and cell death, whether triggered by purified NETs, COVID-19 serum containing high levels of NETs, or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

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“…Almost all DNA glycosylases are inhibited to a certain degree by non-specific single-or double-stranded DNA, competing for binding with substrate DNA [17][18][19][20][21], and a number of modified nucleotides tightly bound but not cleaved when incorporated into oligonucleotides have been described [22][23][24][25][26][27][28]. Moreover, binding and inhibition of DNA glycosylases by polyanions such as heparin [29][30][31][32] likely stems from the ability of these enzymes to bind nucleic acids. Minor-groove ligands of various chemical nature also interfere with DNA glycosylase binding [33,34].…”

Section: Inhibitors Of Dna Glycosylases: General Considerationsmentioning

confidence: 99%

“…The base analog with the strongest ability to suppress Fpg activity (IC 50~1 0-100 µM) is 2-thioxanthine (Table 2); however, it is not a true inhibitor but rather a reagent that oxidizes cysteines in the zinc finger in Fpg, Nei, and NEIL2 [67,68]. MutY from C. pseudotuberculosis was reported to be sensitive to suramin, an antiprotozoan and anthelmintic drug that acts intracellularly [32] (Table 2); however, the relevant drug uptake pathways are likely absent in bacteria. Interestingly, Fpg is strongly inhibited by Cibacron Blue F3GA, a dye bearing structural resemblance to suramin [69] (Table 2).…”

Section: Oxidative Damage Repair: Key To Antibiotic Resistance?mentioning

confidence: 99%

Inhibitors of DNA Glycosylases as Prospective Drugs

Mechetin

Endutkin

Diatlova

et al. 2020

IJMS

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DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy of tumors that have lost alternative repair pathways, such as BRCA-deficient cancers sensitive to poly(ADP-ribose)polymerase inhibition. However, drugs targeting DNA glycosylases are still in development and so far have not advanced to clinical trials. In this review, we cover the attempts to validate DNA glycosylases as suitable targets for inhibition in the pharmacological treatment of cancer, neurodegenerative diseases, chronic inflammation, bacterial and viral infections. We discuss the glycosylase inhibitors described so far and survey the advances in the assays for DNA glycosylase reactions that may be used to screen pharmacological libraries for new active compounds.

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The polyanions heparin and suramin impede binding of free adenine to a DNA glycosylase from C. pseudotuberculosis

Cited by 5 publications

References 51 publications

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

Inhibitors of DNA Glycosylases as Prospective Drugs

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