The influence of the G‐quartet structural integrity on the catalytic activity of the G‐quadruplex(G4)was investigated by comparing the G4‐DNAzyme performances of a series of G4s with a G‐vacancy site and a G‐trip...The influence of the G‐quartet structural integrity on the catalytic activity of the G‐quadruplex(G4)was investigated by comparing the G4‐DNAzyme performances of a series of G4s with a G‐vacancy site and a G‐triplex(G‐tri).The results presented herein not only confirm that the structural integrity of the 3'‐end G‐quartet is necessary for G4s to be catalytically competent but also show how to remediate G‐vacancy‐mediated catalytic activity losses via the addition of guanine surrogates in an approach referred to as G‐vacancy complementation strategy that is applicable to parallel G4s only.Furthermore,this study demonstrates that the terminal G‐quartet could act as a proximal coordinating group and cooperate with the flanking nucleotide to activate the hemin cofactor.展开更多
The structures of human telomeric DNA have received much attention due to its significant biological importance.Most studies have focused on G-quadruplex structure formed by short telomeric DNA sequence,but little is ...The structures of human telomeric DNA have received much attention due to its significant biological importance.Most studies have focused on G-quadruplex structure formed by short telomeric DNA sequence,but little is known about the structures of long singlestranded telomeric DNAs.Here,we investigated the structure of DNA with a long sequence of d[AGGG(TTAGGG)6](G6-DNA)and the effect of a single repeat sequence d(TTAGGG)(G01-DNA)on the structure of G6-DNA using sedimentation velocity technique,polyacrylamide gel electrophoresis,circular dichroism spectroscopy,and UV melting experiments.The results suggest that the G6-DNA can form dimers in aqueous solutions and G01-DNA can form additional G-quadruplex structures by binding to G6-DNA.However,G01-DNA has no effect on the structure of DNA with a sequence of d[AGGG(TTAGGG)3](G3-DNA).Our study provides new insights into the structure polymorphism of long human single-stranded telomeric DNA.展开更多
G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events.G-quadruplexes have become ta...G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events.G-quadruplexes have become targets for anticancer drugs with high selectivity vs.duplex DNA and low cytotoxicity against normal cells.Natural products and their derivatives display polymorphism,structural complexity,and potent activity.It is,therefore,reasonable to seek ligands targeting G-quadruplexes from natural products.Recently,many successful examples have been reported,showing ligands with excellent anticancer activities.In this review,we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.展开更多
G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the fe...G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the feasibility of G-quadruplex structures as drug targets needs to be validated.In this study,Sunitinib,an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex.The stabilization was further enhanced by the combined usage with Berberine,an isoquinoline alkaloid.Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex.The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentage of apoptotic cells reaching about 70%.The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells.This study suggested that more clinic drugs could work by targeting G-quadruplex structures.展开更多
G-quadruplexes attract more and more attention in recent years.Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug developmen...G-quadruplexes attract more and more attention in recent years.Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug development.As a motif existed in physiological condition,flanking sequences are an important part of G-quadruplexes but the study on the impact of flanking sequences on (G-quadruplex)-ligand binding is rarely reported.In this paper,the effects of flanking sequences on binding affinity between a series of unimolecular parallel-stranded G-quadruplex sequences derived from c-myc oncogene promoter (termed as c-myc G-quadruplexes) and their ligands are discussed in detail.The results showed that the flanking sequences on c-myc G-quadruplexes play key roles in (G-quadruplex)-ligand interaction.When a c-myc G-quadruplex is bound to its ligands,the flanking sequences might form a binding cavity above the terminal G-quartet,which could provide a suitable site for ligands to dock in.Moreover,the bases on flanking sequences could interact with ligand through π-π stacking,and finally form a sandwich-stacking mode (terminal G-quartet,ligand and bases on the flanking sequence).This mode could stabilize the (G-quadruplex)-ligand complex effectively and enhance the binding affinity dramatically.However,flanking sequences are also found to exhibit steric hindrance effect which could impede the (G-quadruplex)-ligand binding.展开更多
Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes...Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.展开更多
文摘The influence of the G‐quartet structural integrity on the catalytic activity of the G‐quadruplex(G4)was investigated by comparing the G4‐DNAzyme performances of a series of G4s with a G‐vacancy site and a G‐triplex(G‐tri).The results presented herein not only confirm that the structural integrity of the 3'‐end G‐quartet is necessary for G4s to be catalytically competent but also show how to remediate G‐vacancy‐mediated catalytic activity losses via the addition of guanine surrogates in an approach referred to as G‐vacancy complementation strategy that is applicable to parallel G4s only.Furthermore,this study demonstrates that the terminal G‐quartet could act as a proximal coordinating group and cooperate with the flanking nucleotide to activate the hemin cofactor.
基金supported by the National Natural Scientific Foundation of China (No.21674107)the Fundamental Research Funds for the Central Universities (No.WK2340000066)
文摘The structures of human telomeric DNA have received much attention due to its significant biological importance.Most studies have focused on G-quadruplex structure formed by short telomeric DNA sequence,but little is known about the structures of long singlestranded telomeric DNAs.Here,we investigated the structure of DNA with a long sequence of d[AGGG(TTAGGG)6](G6-DNA)and the effect of a single repeat sequence d(TTAGGG)(G01-DNA)on the structure of G6-DNA using sedimentation velocity technique,polyacrylamide gel electrophoresis,circular dichroism spectroscopy,and UV melting experiments.The results suggest that the G6-DNA can form dimers in aqueous solutions and G01-DNA can form additional G-quadruplex structures by binding to G6-DNA.However,G01-DNA has no effect on the structure of DNA with a sequence of d[AGGG(TTAGGG)3](G3-DNA).Our study provides new insights into the structure polymorphism of long human single-stranded telomeric DNA.
基金supported by the National Natural Science Foundation of China(21172272,21272291)
文摘G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events.G-quadruplexes have become targets for anticancer drugs with high selectivity vs.duplex DNA and low cytotoxicity against normal cells.Natural products and their derivatives display polymorphism,structural complexity,and potent activity.It is,therefore,reasonable to seek ligands targeting G-quadruplexes from natural products.Recently,many successful examples have been reported,showing ligands with excellent anticancer activities.In this review,we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.
基金Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2015RC013)The Fundamental Research Funds for the Central Universities(Grant No.2662017PY113,2662015PY208,2662015BQ048)+2 种基金National Natural Science Foundation of China(Grant No.21502060,21708011)Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343)Open fund of Beijing National Laboratory For Molecular Sciences
文摘G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the feasibility of G-quadruplex structures as drug targets needs to be validated.In this study,Sunitinib,an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex.The stabilization was further enhanced by the combined usage with Berberine,an isoquinoline alkaloid.Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex.The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentage of apoptotic cells reaching about 70%.The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells.This study suggested that more clinic drugs could work by targeting G-quadruplex structures.
文摘G-quadruplexes attract more and more attention in recent years.Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug development.As a motif existed in physiological condition,flanking sequences are an important part of G-quadruplexes but the study on the impact of flanking sequences on (G-quadruplex)-ligand binding is rarely reported.In this paper,the effects of flanking sequences on binding affinity between a series of unimolecular parallel-stranded G-quadruplex sequences derived from c-myc oncogene promoter (termed as c-myc G-quadruplexes) and their ligands are discussed in detail.The results showed that the flanking sequences on c-myc G-quadruplexes play key roles in (G-quadruplex)-ligand interaction.When a c-myc G-quadruplex is bound to its ligands,the flanking sequences might form a binding cavity above the terminal G-quartet,which could provide a suitable site for ligands to dock in.Moreover,the bases on flanking sequences could interact with ligand through π-π stacking,and finally form a sandwich-stacking mode (terminal G-quartet,ligand and bases on the flanking sequence).This mode could stabilize the (G-quadruplex)-ligand complex effectively and enhance the binding affinity dramatically.However,flanking sequences are also found to exhibit steric hindrance effect which could impede the (G-quadruplex)-ligand binding.
基金National Natural Science Foundation of China(Grant No.31701791,21732002,31672558 and 21502060)Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2662017PY113,2015RC013 and 2662015PY208)Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343)。
文摘Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.
