Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Chatzileontiadou, D.S.M.; Tsika, Aikaterini C.; Diamantopoulou, Zoi; Delbé, Jean; Badet, Josette; Courty, José; Skamnaki, Vassiliki T.; Parmenopoulou, Vanessa; Hayes, Joseph M.; Spyroulias, Georgios A.; Leonidas, D.D.

doi:10.1002/cmdc.201700688

Cited by 10 publications

(13 citation statements)

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“…Pyrimidine nucleoside analogues in which a 1,2,3-triazole ring was attached either directly to the C5 position of 2′-deoxyuridine or via a methylene unit were synthesized and exhibited both antiviral activity against herpes simplex viruses, varicella-zoster virus, human cytomegalovirus, vaccinia virus [28][29][30][31] and significant anticancer effects against cancer cell lines PC-3, MDA-MB-231, ACHN [28]. Recently, a series of nucleoside analogues in which the pyrimidine fragment was attached to the ribose moiety at the C1′ carbon via a 1,2,3-triazolyl bridge has been synthesized [32][33][34][35]. No inhibitory activity against HCV virus was observed with any of these compounds, but several C5-substituted 1-β-dribofuranosyl-1,2,3-triazolidomethyluracils showed potent inhibitory activity against RNase A [34] and completely inhibited the angiogenic activity of hAng in vivo [35].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a series of nucleoside analogues in which the pyrimidine fragment was attached to the ribose moiety at the C1′ carbon via a 1,2,3-triazolyl bridge has been synthesized [32][33][34][35]. No inhibitory activity against HCV virus was observed with any of these compounds, but several C5-substituted 1-β-dribofuranosyl-1,2,3-triazolidomethyluracils showed potent inhibitory activity against RNase A [34] and completely inhibited the angiogenic activity of hAng in vivo [35].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

et al. 2020

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Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-triO -acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC 50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC 50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC 50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

et al. 2020

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“…Recent work on RNases’ action within a cellular environment is helping to unravel their natural in vivo substrates (Honda et al, 2015; Lyons et al, 2017; Mesitov et al, 2017). A proper knowledge of the RNases’ active site architecture should lead to the design of specific inhibitors of their biological functions (Chatzileontiadou et al, 2015; Chatzileontiadou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Prats-Ejarque

Salazar

et al. 2019

Front. Pharmacol.

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There is a growing interest in the pharmaceutical industry to design novel tailored drugs for RNA targeting. The vertebrate-specific RNase A superfamily is nowadays one of the best characterized family of enzymes and comprises proteins involved in host defense with specific cytotoxic and immune-modulatory properties. We observe within the family a structural variability at the substrate-binding site associated to a diversification of biological properties. In this work, we have analyzed the enzyme specificity at the secondary base binding site. Towards this end, we have performed a kinetic characterization of the canonical RNase types together with a molecular dynamic simulation of selected representative family members. The RNases’ catalytic activity and binding interactions have been compared using UpA, UpG and UpI dinucleotides. Our results highlight an evolutionary trend from lower to higher order vertebrates towards an enhanced discrimination power of selectivity for adenine respect to guanine at the secondary base binding site (B2). Interestingly, the shift from guanine to adenine preference is achieved in all the studied family members by equivalent residues through distinct interaction modes. We can identify specific polar and charged side chains that selectively interact with donor or acceptor purine groups. Overall, we observe selective bidentate polar and electrostatic interactions: Asn to N1/N6 and N6/N7 adenine groups in mammals versus Glu/Asp and Arg to N1/N2, N1/O6 and O6/N7 guanine groups in non-mammals. In addition, kinetic and molecular dynamics comparative results on UpG versus UpI emphasize the main contribution of Glu/Asp interactions to N1/N2 group for guanine selectivity in lower order vertebrates. A close inspection at the B2 binding pocket also highlights the principal contribution of the protein ß6 and L4 loop regions. Significant differences in the orientation and extension of the L4 loop could explain how the same residues can participate in alternative binding modes. The analysis suggests that within the RNase A superfamily an evolution pressure has taken place at the B2 secondary binding site to provide novel substrate-recognition patterns. We are confident that a better knowledge of the enzymes’ nucleotide recognition pattern would contribute to identify their physiological substrate and eventually design applied therapies to modulate their biological functions.

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“…For comparative purposes, therefore, DEX was also considered in these calculations. There are numerous examples of IFD used to successfully predict ligand-induced protein conformational changes and the effects on biochemical pathways in agreement with experiment [26,32,33,34,35], including for GR [26]. The results of the IFD are shown in Table 1, with both PPD and PPT predicted to bind well.…”

Section: Resultsmentioning

confidence: 77%

Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol

Karra

Konstantinou

Tzortziou

et al. 2018

IJMS

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Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist.

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Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Cited by 10 publications

References 58 publications

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol

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