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16 pages, 4598 KiB

Open AccessArticle

Stability of Human Telomeric G-Quadruplexes Complexed with Photosensitive Ligands and Irradiated with Visible Light

by Valeria Libera, Francesca Ripanti, Caterina Petrillo, Francesco Sacchetti, Javier Ramos-Soriano, Maria Carmen Galan, Giorgio Schirò, Alessandro Paciaroni and Lucia Comez

Int. J. Mol. Sci. 2023, 24(10), 9090; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109090 - 22 May 2023

Cited by 1 | Viewed by 1374

Abstract

Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, [...] Read more.

Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, molecular probe applications, and biosensing. In recent years, the use of G4-ligand complexes as photopharmacological targets has shown significant promise for developing novel therapeutic strategies and nanodevices. Here, we studied the possibility of manipulating the secondary structure of a human telomeric G4 sequence through the interaction with two photosensitive ligands, DTE and TMPyP4, whose response to visible light is different. The effect of these two ligands on G4 thermal unfolding was also considered, revealing the occurrence of peculiar multi-step melting pathways and the different attitudes of the two molecules on the quadruplex stabilization. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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23 pages, 9178 KiB

Open AccessArticle

Novel Chiral Ru(II) Complexes as Potential c-myc G-quadruplex DNA Stabilizers Inducing DNA Damage to Suppress Triple-Negative Breast Cancer Progression

by Chanling Yuan, Zhixiang Wang, Zongtao Wang, Wentao Liu, Guohu Li, Jinlan Meng, Ruzhen Wu, Qiong Wu, Jiacheng Wang and Wenjie Mei

Int. J. Mol. Sci. 2023, 24(1), 203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010203 - 22 Dec 2022

Cited by 3 | Viewed by 1408

Abstract

Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy [...] Read more.

Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy to fight cancer. Herein, a series of chiral ruthenium(II) complexes ([Ru(bpy)₂(DPPZ-R)](ClO₄)₂, Λ/Δ−1: R = -H, Λ/Δ−2: R = -Br, Λ/Δ−3: R = -C≡C(C₆H₄)NH₂) were researched based on their interaction with c-myc G-quadruplex DNA. Λ−3 and Δ−3 show high affinity and stability to decrease their replication. Additional studies showed that Λ−3 and Δ−3 exhibit higher inhibition against different tumor cells than other molecules. Δ−3 decreases the viability of MDA-MB-231 cells with an IC₅₀ of 25.51 μM, which is comparable with that of cisplatin, with an IC₅₀ of 25.9 μM. Moreover, Δ−3 exhibits acceptable cytotoxic activity against MDA-MB-231 cells in a zebrafish xenograft breast cancer model. Further studies suggested that Δ−3 decreases the viability of MDA-MB-231 cells predominantly through DNA-damage-mediated apoptosis, which may be because Δ−3 can induce DNA damage. In summary, the results indicate that Ru(II) complexes containing alkinyl groups can be developed as c-myc G-quadruplex DNA binders to block TNBC progression. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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16 pages, 5044 KiB

Open AccessArticle

Investigation of the Interaction between Aloe vera Anthraquinone Metabolites and c-Myc and C-Kit G-Quadruplex DNA Structures

by Sabrina Dallavalle, Roberto Artali, Salvatore Princiotto, Loana Musso, Gigliola Borgonovo and Stefania Mazzini

Int. J. Mol. Sci. 2022, 23(24), 16018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416018 - 16 Dec 2022

Cited by 1 | Viewed by 1187

Abstract

G-quadruplexes are nucleotide sequences present in the promoter region of numerous oncogenes, having a key role in the suppression of gene transcription. Recently, the binding of anthraquinones from Aloe vera to G-quadruplex structures has been studied through various physico-chemical techniques. Intrigued by the [...] Read more.

G-quadruplexes are nucleotide sequences present in the promoter region of numerous oncogenes, having a key role in the suppression of gene transcription. Recently, the binding of anthraquinones from Aloe vera to G-quadruplex structures has been studied through various physico-chemical techniques. Intrigued by the reported results, we investigated the affinity of aloe emodin, aloe emodin-8-glucoside, and aloin to selected G-quadruplex nucleotide sequences by NMR spectroscopy. The structural determinants for the formation of the ligand/nucleotide complexes were elucidated and a model of the interactions between the tested compounds and C-Kit and c-Myc G-quadruplex DNA structures was built by integrated NMR and molecular modeling studies. Overall, the obtained results confirmed and implemented the previously reported findings, pointing out the complementarity of the different approaches and their contribution to a more detailed overview of the ligand/nucleotide complex formation. Furthermore, the proposed models of interaction could pave the way to the design of new nature-derived compounds endowed with increased G-quadruplex stabilizing activity. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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12 pages, 1586 KiB

Open AccessArticle

Properties and Potential Antiproliferative Activity of Thrombin-Binding Aptamer (TBA) Derivatives with One or Two Additional G-Tetrads

by Daniela Benigno, Antonella Virgilio, Ivana Bello, Sara La Manna, Valentina Vellecco, Mariarosaria Bucci, Daniela Marasco, Elisabetta Panza, Veronica Esposito and Aldo Galeone

Int. J. Mol. Sci. 2022, 23(23), 14921; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314921 - 29 Nov 2022

Cited by 3 | Viewed by 1303

Abstract

In this paper, we study the biological properties of two TBA analogs containing one and two extra G-tetrads, namely TBAG3 and TBAG4, respectively, and two further derivatives in which one of the small loops at the bottom (TBAG41S) or the large loop at [...] Read more.

In this paper, we study the biological properties of two TBA analogs containing one and two extra G-tetrads, namely TBAG3 and TBAG4, respectively, and two further derivatives in which one of the small loops at the bottom (TBAG41S) or the large loop at the top (TBAG4GS) of the TBAG4 structure has been completely modified by replacing all loop residues with abasic site mimics. The therapeutical development of the TBA was hindered by its low thermodynamic and nuclease stability, while its potential as an anticancer/antiproliferative molecule is also affected by the anticoagulant activity, being a side effect in this case. In order to obtain suitable TBA analogs and to explore the involvement of specific aptamer regions in biological activity, the antiproliferative capability against DU 145 and MDAMB 231 cancer cell lines (MTT), the anticoagulant properties (PT), the biological degradability (nuclease stability assay) and nucleolin (NCL) binding ability (SPR) of the above described TBA derivatives have been tested. Interestingly, none of the TBA analogs exhibits an anticoagulant activity, while all of them show antiproliferative properties to the same extent. Furthermore, TBAG4 displays extraordinary nuclease stability and promising antiproliferative properties against breast cancer cells binding NCL efficiently. These results expand the range of G4-structures targeting NCL and the possibility of developing novel anticancer and antiviral drugs. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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12 pages, 1786 KiB

Open AccessArticle

Novel Planar Pt(II) Cyclometallated Cytotoxic Complexes with G-Quadruplex Stabilisation and Luminescent Properties

by Brondwyn S. McGhie, Jennette Sakoff, Jayne Gilbert, Christopher P. Gordon and Janice R. Aldrich-Wright

Int. J. Mol. Sci. 2022, 23(18), 10469; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810469 - 09 Sep 2022

Cited by 7 | Viewed by 1229

Abstract

Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square–planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was [...] Read more.

Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square–planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was determined in two of the major G-quadruplex structures formed in the human c-MYC promoter gene (c-MYC) and a human telomeric repeat sequence (H-Telo). The CMCs were found to stabilise H-telo more strongly than c-MYC, and the CMCs with the highest cytotoxic effect had a low–moderate correlation between H-telo binding capacity and cytotoxicity (R² values up to 10 times those of c-MYC). The melting experiments further revealed that the stabilisation effect was altered depending on whether the CMC was introduced before or after the formation of QDNA. All CMCs’ GI₅₀ values were comparable or better than cisplatin in human cancer cell lines HT29, U87, MCF-7, H460, A431, Du145, BE2-C, SJ-G2, MIA, and ADDP. Complexes 6, 7, and 9 were significantly more cytotoxic than cisplatin in all cell lines tested and had good to moderate selectivity indices, 1.7–4.5 in MCF10A/MCF-7. The emission quantum yields were determined to be relatively high (up to 0.064), and emission occurred outside cellular autofluorescence, meaning CMC fluorescence is ideal for in vitro analyses. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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18 pages, 2189 KiB

Open AccessArticle

Impact of G-Quadruplex Structures on Methylation of Model Substrates by DNA Methyltransferase Dnmt3a

by Andrei G. Loiko, Alexander V. Sergeev, Adelya I. Genatullina, Mayya V. Monakhova, Elena A. Kubareva, Nina G. Dolinnaya and Elizaveta S. Gromova

Int. J. Mol. Sci. 2022, 23(18), 10226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810226 - 06 Sep 2022

Cited by 1 | Viewed by 1587

Abstract

In mammals, de novo methylation of cytosines in DNA CpG sites is performed by DNA methyltransferase Dnmt3a. Changes in the methylation status of CpG islands are critical for gene regulation and for the progression of some cancers. Recently, the potential involvement of DNA [...] Read more.

In mammals, de novo methylation of cytosines in DNA CpG sites is performed by DNA methyltransferase Dnmt3a. Changes in the methylation status of CpG islands are critical for gene regulation and for the progression of some cancers. Recently, the potential involvement of DNA G-quadruplexes (G4s) in methylation control has been found. Here, we provide evidence for a link between G4 formation and the function of murine DNA methyltransferase Dnmt3a and its individual domains. As DNA models, we used (i) an isolated G4 formed by oligonucleotide capable of folding into parallel quadruplex and (ii) the same G4 inserted into a double-stranded DNA bearing several CpG sites. Using electrophoretic mobility shift and fluorescence polarization assays, we showed that the Dnmt3a catalytic domain (Dnmt3a-CD), in contrast to regulatory PWWP domain, effectively binds the G4 structure formed in both DNA models. The G4-forming oligonucleotide displaced the DNA substrate from its complex with Dnmt3a-CD, resulting in a dramatic suppression of the enzyme activity. In addition, a direct impact of G4 inserted into the DNA duplex on the methylation of a specific CpG site was revealed. Possible mechanisms of G4-mediated epigenetic regulation may include Dnmt3a sequestration at G4 and/or disruption of Dnmt3a oligomerization on the DNA surface. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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20 pages, 2394 KiB

Open AccessArticle

Modulation of Aptamer–Ligand-Binding by Complementary Oligonucleotides: A G-Quadruplex Anti-Ochratoxin A Aptamer Case Study

by Alexey V. Samokhvalov, Irina V. Safenkova, Sergei A. Eremin, Artem N. Bonchuk, Oksana G. Maksimenko, Nikolai N. Sluchanko, Anatoly V. Zherdev and Boris B. Dzantiev

Int. J. Mol. Sci. 2022, 23(9), 4876; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094876 - 28 Apr 2022

Cited by 4 | Viewed by 2062

Abstract

Short oligonucleotides are widely used for the construction of aptamer-based sensors and logical bioelements to modulate aptamer–ligand binding. However, relationships between the parameters (length, location of the complementary region) of oligonucleotides and their influence on aptamer–ligand interactions remain unclear. Here, we addressed this [...] Read more.

Short oligonucleotides are widely used for the construction of aptamer-based sensors and logical bioelements to modulate aptamer–ligand binding. However, relationships between the parameters (length, location of the complementary region) of oligonucleotides and their influence on aptamer–ligand interactions remain unclear. Here, we addressed this task by comparing the effects of short complementary oligonucleotides (ssDNAs) on the structure and ligand-binding ability of an aptamer and identifying ssDNAs’ features that determine these effects. Within this, the interactions between the OTA-specific G-quadruplex aptamer 1.12.2 (5′-GATCGGGTGTGGGTGGCGTAAAGGGA GCATCGGACA-3′) and 21 single-stranded DNA (ssDNA) oligonucleotides complementary to different regions of the aptamer were studied. Two sets of aptamer–ssDNA dissociation constants were obtained in the absence and in the presence of OTA by isothermal calorimetry and fluorescence anisotropy, respectively. In both sets, the binding constants depend on the number of hydrogen bonds formed in the aptamer–ssDNA complex. The ssDNAs’ having more than 23 hydrogen bonds with the aptamer have a lower aptamer dissociation constant than for aptamer–OTA interactions. The ssDNAs’ having less than 18 hydrogen bonds did not affect the aptamer–OTA affinity. The location of ssDNA’s complementary site in the aptamer affeced the kinetics of the interaction and retention of OTA-binding in aptamer–ssDNA complexes. The location of the ssDNA site in the aptamer G-quadruplex led to its unfolding. In the presence of OTA, the unfolding process was longer and takes from 20 to 70 min. The refolding in the presence of OTA was possible and depends on the length and location of the ssDNA’s complementary site. The location of the ssDNA site in the tail region led to its rapid displacement and wasn’t affecting the G-qaudruplex’s integrity. It makes the tail region more perspective for the development of ssDNA-based tools using this aptamer. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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Review

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16 pages, 725 KiB

Open AccessReview

G-Quadruplexes in Repeat Expansion Disorders

by Ye Teng, Ming Zhu and Zhidong Qiu

Int. J. Mol. Sci. 2023, 24(3), 2375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032375 - 25 Jan 2023

Cited by 3 | Viewed by 1981

Abstract

The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported [...] Read more.

The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported to form functional G-quadruplexes, participating in many important bioprocesses. In this review, we conducted an overview concerning the contribution of G-quadruplex in repeat expansion disorders and summarized related mechanisms in current pathological studies, including the increasing genetic instabilities in replication and transcription, the toxic RNA foci formed in neurons, and the loss/gain function of proteins and peptides. Furthermore, novel strategies targeting G-quadruplex repeats were developed based on the understanding of disease mechanism. Small molecules and proteins binding to G-quadruplex in repeat expansions were investigated to protect neurons from dysfunction and delay the progression of neurodegeneration. In addition, the effects of environment on the stability of G-quadruplex were discussed, which might be critical factors in the pathological study of repeat expansion disorders. Full article

(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0)

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