Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

Xiong, Ye; Huang, Zhi‐Shu; Tan, Jia‐Heng

doi:10.1016/j.ejmech.2014.11.021

Cited by 67 publications

(31 citation statements)

References 140 publications

(155 reference statements)

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“…The involvement of G4 structures in several human diseases propelled the development of small molecules directed against G4s 7,29 . However, only very few have been tested against viruses, i.e.…”

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confidence: 99%

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro

Perrone

Scalabrin

et al. 2017

Sci Rep

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G-quadruplexes (G4s) are nucleic acids secondary structures, epigenetic regulators in cells and viruses. In herpes simplex virus 1 (HSV-1)-infected cells, G4s are massively present during viral replication. We here aimed at investigating the possibility to target the HSV-1 G4s by a core extended naphtalene diimide (c-exNDI) G4 ligand. Biophysical and biomolecular analysis proved that c-exNDI stabilized the HSV-1 G4s in a concentration dependent manner. In MS competition assays, c-exNDI preferentially recognized HSV-1 G4s over cellular telomeric G4s, the most represented G4s within cells; other less abundant cellular G4s were also recognized. Treatment of HSV-1 infected cells with c-exNDI at low nanomolar concentrations induced significant virus inhibition with no cytotoxicity. The mechanism of action was ascribed to G4-mediated inhibition of viral DNA replication, with consequent impairment of viral genes transcription. Our data suggest that the observed potent antiviral activity and low cytotoxicity mainly depend on a combination of c-exNDI affinity for HSV-1 G4s and their massive presence during infection. HSV-1 G4s may thus represent new effective antiviral targets: the fact that no current antiherpetic drug exploits them and their presence at the viral genome, responsible for both active and latent HSV infections, makes them particularly attracting.

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mentioning

confidence: 99%

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro

Perrone

Scalabrin

et al. 2017

Sci Rep

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“…The ∆T m of F21T varied considerably in presence of these three alkaloids, although molecular modeling methods suggest almost the similar mode of interactions and comparable binding energies in the hybrid 3+1 topology [64]. Non-electrostatic interactions in the binding of small molecules to G4 are preferable for telomerase inhibition under physiological conditions [60]. Amongst the alkaloids tested here, chelidonine is estimated to have less non-electrostatic interactions than the others as it has an extra hydroxyl group and lesser number of aromatic rings.…”

Section: The Alkaloids Generally Inhibited Both Telomerase and Taq Pomentioning

confidence: 98%

Selectivity of major isoquinoline alkaloids from Chelidonium majus towards telomeric G-quadruplex: A study using a transition-FRET (t-FRET) assay

Noureini

Esmaeili

Abachi

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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BackgroundNatural bioproducts are invaluable resources in drug discovery. Isoquinoline alkaloids of Chelidonium majus constitute a structurally diverse family of natural products that are of great interest, one of them being their selectivity for human telomeric G-quadruplex structure and telomerase inhibition. MethodsThe study focuses on the mechanism of telomerase inhibition by stabilization of telomeric Gquadruplex structures by berberine, chelerythrine, chelidonine, sanguinarine and papaverine. Telomerase activity and mRNA levels of hTERT were estimated using quantitative telomere repeat amplification protocol and qPCR, in MCF-7 cells treated with different groups of alkaloids. The selectivity of the main isoquinoline alkaloids of Chelidonium majus towards telomeric Gquadruplex forming sequences were explored using a sensitive modified thermal FRET-melting measurement in the presence of the complementary oligonucleotide CT22. We assessed and monitored G-quadruplex topologies using circular dichroism (CD) methods, and compared spectra to previously well-characterized motifs, either alone or in the presence of the alkaloids, Molecular modeling was performed to rationalize ligand binding to the G-quadruplex structure. ResultsThe results highlight strong inhibitory effects of chelerythrine, sanguinarine and berberine on telomerase activity, most likely through substrate sequestration. These isoquinoline alkaloids interacted strongly with telomeric sequence G-quadruplex. In comparison, chelidonine and papaverine had no significant interaction with the telomeric quadruplex, while they strongly inhibited telomerase at transcription level of hTERT. Altogether, all of the studied alkaloids showed various levels and mechanisms of telomerase inhibition. ConclusionsWe report on a comparative study of anti-telomerase activity of the isoquinoline alkaloids of Chelidonium majus. Chelerythrine was most effective in inhibiting telomerase activity by substrate sequesteration through G-quadruplex stabilization. General SignificanceUnderstanding structural and molecular mechanisms of anti-cancer agents can help in developing new and more potent drugs with fewer side effects. Isoquinolines are the most biologically active agents from Chelidonium majus, which have shown to be telomeric G-quadruplex stabilizers and potent telomerase inhibitors.

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“…16 G4 DNA was also targeted with heterocyclic alkaloids and their derivatives, such as palmatine, sanguarine, berberine ( 1 ) and coralyne ( 2 ). 17 In this context, absorption and fluorescence studies with intramolecular anti-parallel G-quadruplex forming human telomeric TTAGGG repeat sequences revealed non-cooperative 1 : 1 binding for all the molecules, with 2 having a stronger binding affinity than the related alkaloids. 18 Coralyne ( 2 ) also stabilizes G4 DNA more efficiently against thermal denaturation and it has a higher anti-telomerase activity (IC 50 = 70 μM) than berberine ( 1 ).…”

Section: Introductionmentioning

confidence: 97%

8-Styryl-substituted coralyne derivatives as DNA binding fluorescent probes

et al. 2017

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Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

Cited by 67 publications

References 140 publications

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Selectivity of major isoquinoline alkaloids from Chelidonium majus towards telomeric G-quadruplex: A study using a transition-FRET (t-FRET) assay

8-Styryl-substituted coralyne derivatives as DNA binding fluorescent probes

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