Polymorphism of human telomeric quadruplexes with drugs: a multi-technique biophysical study

Comez, Lucia; Bianchi, F.; Libera, Valeria; Longo, Marialucia; Petrillo, C.; Sacchetti, F.; Sebastiani, Federico; D’Amico, Francesco; Rossi, Barbara; Gessini, Alessandro; Masciovecchio, C.; Amenitsch, Heinz; Sissi, Claudia; Paciaroni, Alessandro

doi:10.1039/d0cp01483d

Cited by 21 publications

(19 citation statements)

References 58 publications

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“…and because of their intrinsically highly dynamic character [14]. Therefore, many different and biologically relevant quadruplex structures have been characterized and reported over the last years and, in particular, the human telomeric structure polymorphism, and the effects observed upon ligand binding, have been the object of intense investigation [15][16][17][18][19][20]. The telomeric sequence displays a pronounced polymorphism and several structures have been characterized, predominantly the hybrid mixture and antiparallel and parallel topologies [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

Gratal

Quero

Pérez‐Redondo

et al. 2021

IJMS

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A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).

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Section: Introductionmentioning

confidence: 99%

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

Gratal

Quero

Pérez‐Redondo

et al. 2021

IJMS

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“…The rationale of using a K + solution is its biological relevance due to the high intracellular concentration of K + (∼140 mM) . Under these conditions, Tel22 is a mixture of two (3+1) hybrid-type (H) and basket-type topologies; complexation with small molecules may significantly alter the equilibrium of these two different conformers. − …”

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confidence: 99%

Porphyrin Binding and Irradiation Promote G-Quadruplex DNA Dimeric Structure

Libera

Андреева

Martel

et al. 2021

J. Phys. Chem. Lett.

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Nucleic acid sequences rich in guanines can organize into noncanonical DNA G-quadruplexes (G4s) of variable size. The design of small molecules stabilizing the structure of G4s is a rapidly growing area for the development of novel anticancer therapeutic strategies and bottom-up nanotechnologies. Among a multitude of binders, porphyrins are very attractive due to their light activation that can make them valuable conformational regulators of G4s. Here, a structure-based strategy, integrating complementary probes, is employed to study the interaction between TMPyP4 porphyrin and a 22-base human telomeric sequence (Tel22) before and after irradiation with blue light. Porphyrin binding is discovered to promote Tel22 dimerization, while light irradiation of the Tel22-TMPyP4 complex controls dimer fraction. Such a change in quaternary structure is found to be strictly correlated with modifications at the secondary structure level, thus providing an unprecedented link between the degree of dimerization and the underlying conformational changes in G4s.

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“…From the analysis, it is clear that both L1 and L2 induce a parallel G‐quadruplex, (Figure 5 and S14–17). An alternative analysis strategy has been described by Paciaroni and co‐workers [35] …”

Section: Resultsmentioning

confidence: 99%

“…An alternative analysiss trategy has been described by Paciaroniand co-workers. [35] The G-quadruplexes induced by L1 are stabilised significantly compared to the initial hybrid conformation.T he melting temperature of the parallel G-quadruplex inducedb y1 0equiv of L1 is certainly high, but cannot be calculated from the data, as the G-quadruplex structure is still not fully denatured at 95 8C. Upon addition of only 2equiv of L1,asignificant stabilisation of 14.9 8Cc ould be determined.…”

Section: Resultsmentioning

confidence: 99%

Triggering G‐Quadruplex Conformation Switching with [7]Helicenes

Lousen

Pedersen

Răsădean

et al. 2021

Chemistry A European J

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The dynamic interplay between two types of chiral structures; fully conjugated racemic hetero[7]helicenes and DNA strands prone to fold into G‐quadruplex structures is described. Both the [7]helicenes and the G‐quadruplex DNA structures exist in more than one conformation in solution. We show that the structures interact with and stabilise each other, mutually amplifying and stabilising certain conformations at increased temperatures. The [7]helicene ligands L1 and L2 stabilise the parallel conformation of k‐ras significantly, whereas hybrid (K+) and antiparallel (Na+) h‐telo G‐quadruplexes are stabilised upon conformational switching into altered G‐quadruplex conformations. Both L1 and L2 induce parallel G‐quadruplexes from hybrid structures (K+) and L1 induces hybrid G‐quadruplexes from antiparallel conformations (Na+). Enantioselective binding of one helicene enantiomer is observed for helicene ligand L2, and VTCD melting experiments are used to estimate the racemisation barrier of the helicene.

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Polymorphism of human telomeric quadruplexes with drugs: a multi-technique biophysical study

Abstract: A multi-technique biophysical method is used to study the ligand binding to G-quadruplex DNA.

Cited by 21 publications

References 58 publications

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

PhenQE8, a Novel Ligand of the Human Telomeric Quadruplex

Porphyrin Binding and Irradiation Promote G-Quadruplex DNA Dimeric Structure

Triggering G‐Quadruplex Conformation Switching with [7]Helicenes

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