Article
Biochemistry & Molecular Biology
Pauline Lejault, Louis Prudent, Michel-Pierre Terrier, Jean-Pierre Perreault
Summary: RNA G-quadruplexes (rG4) have emerged as important regulatory elements in RNA. Specific ligands have been developed to bind to rG4s and their role in the folding of rG4 structures is still unclear. In this study, in vitro techniques were used to examine the binding capacity of five G4 ligands to induce rG4 structures. It was found that PhenDC3 and PDS can induce rG4 formation in single RNA strands.
Review
Biochemistry & Molecular Biology
Anzhela Pavlova, Elena A. Kubareva, Mayya Monakhova, Maria Zvereva, Nina G. Dolinnaya
Summary: DNA G-quadruplexes are crucial components of regulatory systems in cells and impact genome integrity by impeding DNA replication. Recent studies have focused on the role of G4s in genomic instability and DNA repair processes, highlighting the intricate balance between stability and instability in the genome.
Article
Biochemistry & Molecular Biology
Andrei G. Loiko, Alexander Sergeev, Adelya Genatullina, Mayya Monakhova, Elena A. Kubareva, Nina G. Dolinnaya, Elizaveta S. Gromova
Summary: This study reveals a potential link between G-quadruplex formation and the function of DNA methyltransferase Dnmt3a in mammals. G4s may play a role in epigenetic regulation by affecting the methylation of specific CpG sites and modulating the enzyme activity. Possible mechanisms include sequestration of Dnmt3a at G4 structures and disruption of Dnmt3a oligomerization on DNA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Chiara Platella, Francesca Ghirga, Domenica Musumeci, Deborah Quaglio, Pasquale Zizza, Sara Iachettini, Carmen D'Angelo, Annamaria Biroccio, Bruno Botta, Mattia Mori, Daniela Montesarchio
Summary: In this study, five natural compounds were investigated as analogs of promising G-quadruplex-targeting ligands to identify highly effective and selective anticancer candidates. Among them, Dicentrine was found to be the most effective ligand for telomeric and oncogenic G-quadruplexes, showing good selectivity. In-depth studies demonstrated that Dicentrine thermally stabilizes G-quadruplexes without affecting the control duplex, with higher affinity for G-quadruplex structures. Molecular dynamics simulations indicated that Dicentrine preferentially binds the G-quadruplex groove or the outer G-tetrad. Biological assays confirmed that Dicentrine promotes potent and selective anticancer activity by inducing cell cycle arrest through apoptosis, targeting G-quadruplex structures at telomeres.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Multidisciplinary Sciences
Sagar Bag, Mangal Deep Burman, Sudipta Bhowmik
Summary: G-quadruplex is a unique structure in nucleic acids that exists widely in human genome and has attracted great attention in therapeutic investigations. Targeting G-quadruplex structure is a new strategy for drug development. Flavonoids, which are present in various dietary plant-based products, have shown high pharmacological effectiveness with minimal cytotoxicity, making them potential alternatives to synthetic therapeutic medicines. Research on the interaction between G-quadruplex and flavonoids is expected to provide newer perspectives for the development of novel therapeutic agents.
Review
Chemistry, Multidisciplinary
Robert C. Monsen
Summary: G-quadruplexes (G4s) are secondary structures in nucleic acids formed in guanine-rich regions. They are abundant in the genome, especially in gene promoter regions. G4s function as epigenetic features and binding centers for transcription factors. Stabilizing or disrupting G4s in gene promoters directly affects adjacent gene transcription, making them potential drug targets for hard-to-target proteins in cancer. However, the lack of distinctive receptor structures and off-target effects have hindered the progress of G4 ligands in clinical trials. This review suggests shifting the focus to higher-order G4 structures as selective molecular targets.
FRONTIERS IN CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Tingjie Song, Xiaojing Wang, Dongbao Yao, Haojun Liang, Yi Lu
Summary: This study successfully identified and differentiated G4 DNA molecules with different topologies and nucleotide residues using synthetic G4 DNA-encoded nanoparticle approach, and validated the effectiveness and sensitivity of this method through monitoring plasmonic properties.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Marc-Antoine Turcotte, Jean-Michel Garant, Helene Cossette-Roberge, Jean-Pierre Perreault
Summary: This study identified the presence of G-quadruplex regulation in neurodegenerative diseases and demonstrated the folding of G4 sequences in the 5' untranslated regions of mRNAs associated with Parkinson's disease. The G4s significantly repressed the translation of Parkin RBR E3 Ubiquitin Protein Ligase (PRKN) and Vacuolar Protein Sorting-Associated Protein 35 (VPS35) in neuronal cells, and a novel G4-binding protein, GNL1, was identified through RNA affinity purification assays.
Article
Biochemistry & Molecular Biology
Dana Beseiso, Erin Chen, Sawyer E. McCarthy, Kailey N. Martin, Elizabeth P. Gallagher, Joanne Miao, Liliya A. Yatsunyk
Summary: G-quadruplexes (GQs) are DNA structures composed of stabilized G-tetrads. This study investigates telomeric DNA variants from Tetrahymena thermophila and solves the crystal structure of two variants, revealing new GQ structures. The results expand our understanding of telomeric repeats and GQs in general.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Swati Chaudhary, Mohan Kumar, Mahima Kaushik
Summary: G-quadruplexes play significant roles in various diseases and have been extensively studied. Further understanding of these structures and their stabilizing or destabilizing ligands can facilitate future drug discovery.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Qin-Xia Song, Chang -Wei Lai, Na-Nv Liu, Xi-Miao Hou, Xu-Guang Xi
Summary: The G4 DNA binding protein Dbp2 has been found to prefer G-rich substrates and plays a dual role in destabilizing and inducing further folding of MycG4 structures. It may also participate in DNA metabolism.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Medicine, Research & Experimental
Florian J. Groelly, Manuela Porru, Jutta Zimmer, Hugo Benainous, Yanti De Visser, Anastasiya A. Kosova, Serena Di Vito, Violeta Serra, Anderson Ryan, Carlo Leonetti, Alejandra Bruna, Annamaria Biroccio, Madalena Tarsounas
Summary: The compound pyridostatin shows high specificity against BRCA1/2-deficient tumors and tumors resistant to PARP inhibitors. It disrupts replication leading to DNA double-stranded breaks and can be repaired in the absence of BRCA1/2 by non-homologous end joining. Additionally, pyridostatin triggers immune responses and can be further potentiated by combining it with paclitaxel. Overall, pyridostatin has potential for therapeutic development in cancer patients with BRCA1/2 mutations.
EMBO MOLECULAR MEDICINE
(2022)
Article
Chemistry, Medicinal
Mao-Lin Li, Jing-Mei Yuan, Hao Yuan, Bi-Han Wu, Shi-Liang Huang, Qing-Jiang Li, Tian-Miao Ou, Hong-Gen Wang, Jia-Heng Tan, Ding Li, Shuo-Bin Chen, Zhi-Shu Huang
Summary: Research suggests that drugs targeting G4 structures and improving anti-tumor activity through the introduction of carbohydrates could be a promising option for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Poulomi Das, Khac Huy Ngo, Fernaldo Richtia Winnerdy, Arijit Maity, Blaz Bakalar, Yves Mechulam, Emmanuelle Schmitt, Anh Tuan Phan
Summary: This study investigates the adaptability of left-handed G4 structures towards the presence of bulges, presenting the structural characteristics of left-handed G4s accommodating varying numbers of bulges. Bulges in left-handed G4s exhibit distinct features compared to those in right-handed G4s, and elucidation of the intricate structural details may enhance understanding of the potential roles and limitations of these unique structures.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Chemistry, Multidisciplinary
Luying Chen, Jonathan Dickerhoff, Saburo Sakai, Danzhou Yang
Summary: DNA G-quadruplexes formed in human telomeres and oncogene promoters are functionally important and have emerged as a promising class of cancer-specific drug targets. In this article, the authors discuss their efforts to understand the structures and functions of these DNA G-quadruplexes and their interactions with small molecules. They have determined the high-resolution structures of telomeric G-quadruplexes and studied G-quadruplexes formed in key oncogene promoters. The authors also highlight the potential of G-quadruplexes as selectively targetable drug receptors and discuss their recent discoveries of small molecules that specifically recognize these G-quadruplexes. Overall, this work provides a strong foundation for future research on G-quadruplexes and the design of G-quadruplex-targeted drugs.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Article
Biotechnology & Applied Microbiology
Olga Minenkova, Daniela Santapaola, Ferdinando Maria Milazzo, Anna Maria Anastasi, Gianfranco Battistuzzi, Caterina Chiapparino, Antonio Rosi, Giuseppe Gritti, Gianmaria Borleri, Alessandro Rambaldi, Clelia Dental, Cecile Viollet, Bruno Pagano, Laura Salvini, Emanuele Marra, Laura Luberto, Antonio Rossi, Anna Riccio, Emilio Merlo Pich, Maria Gabriella Santoro, Rita De Santis
Summary: A study has identified a human single chain antibody called 76clAbs that can block a key site on the SARS-CoV-2 spike protein, neutralize the Delta variant and other variants, and inhibit critical pathological features of COVID-19. Administered intranasally, it effectively combated infection in animal models. Therefore, 76clAbs may serve as a rapid and self-administrable early intervention tool independent of the immune status of SARS-CoV-2-infected individuals.
Article
Endocrinology & Metabolism
Ugo Chianese, Chiara Papulino, Eugenia Passaro, Tom MJ. Evers, Mehrad Babaei, Antonella Toraldo, Tommaso De Marchi, Emma Nimeus, Vincenzo Carafa, Maria Maddalena Nicoletti, Nunzio Del Gaudio, Nunzia Iaccarino, Antonio Randazzo, Dante Rotili, Antonello Mai, Salvatore Cappabianca, Alireza Mashaghi, Fortunato Ciardiello, Lucia Altucci, Rosaria Benedetti
Summary: This paper focuses on the aberrant activity of androgen receptor (AR) in prostate cancer (PCa) and castration-resistant PCa (CRPC), and how it can be regulated by epigenetic factors. The study explores the role of lysine-specific demethylases (KDMs) in regulating the transcriptional program of AR and highlights their potential use in resistance to androgen deprivation therapy.
MOLECULAR METABOLISM
(2022)
Article
Chemistry, Medicinal
Roberta Rocca, Nicoletta Polera, Giada Juli, Katia Grillone, Annalisa Maruca, Maria Teresa Di Martino, Anna Artese, Jussara Amato, Bruno Pagano, Antonio Randazzo, Pietrosandro Tagliaferri, Pierfrancesco Tassone, Stefano Alcaro
Summary: RNA is currently a target of interest for the design of new small molecules with diverse pharmacological activities. Among these RNA molecules, long noncoding RNAs (lncRNAs) have been extensively associated with cancer pathogenesis. In particular, the overexpression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the development of multiple myeloma (MM). By utilizing the crystallographic structure of the triple-helical stability element of MALAT1, a structure-based virtual screening was conducted on a large commercial database, and five compounds were selected for in vitro assays. Among them, compound M5 showed the most promising results, destabilizing the MALAT1 triplex structure and demonstrating antiproliferative activity in MM cell models. M5 is suggested as a lead compound for further optimization to enhance its affinity towards MALAT1.
ARCHIV DER PHARMAZIE
(2023)
Article
Cell & Tissue Engineering
Maria Rosaria Ambrosio, Teresa Migliaccio, Fabiana Napolitano, Sarah Di Somma, Giovanni Maneli, Jussara Amato, Bruno Pagano, Antonio Randazzo, Giuseppe Portella, Pietro Formisano, Anna Maria Malfitano
Summary: In this study, the role of G4 motifs in adipogenic differentiation was investigated using human adipose-derived mesenchymal stem cells (ASCs). The results showed that G4 structures were increased in differentiated adipocytes compared to their precursors, and treatment with the G4 ligand Braco-19 reduced G4 content in the mature adipocytes. Furthermore, Braco-19 caused morphological changes and reduced lipid droplet formation and key gene expression in the mature adipocytes. These findings reveal a new role of G4 motifs in human adipocyte differentiation.
STEM CELL RESEARCH & THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Silvia Trombetti, Nunzia Iaccarino, Patrizia Riccio, Raffaele Sessa, Rosa Catapano, Marcella Salvatore, Stelina Luka, Sergio de Nicola, Paola Izzo, Sante Roperto, Pasqualino Maddalena, Antonio Randazzo, Michela Grosso
Summary: Ferroptosis is a regulated cell death involving lipid peroxidation. GPX4 plays a central role in its regulation. Ferroptosis is connected to lipid metabolism, cancer onset, and drug resistance. GATA-1 isoforms, particularly GATA-1(S), are involved in hematological malignancies. Overexpression of GATA-1(S) prevents ferroptosis in leukemia cells. Targeting ferroptosis is a promising strategy to overcome drug resistance in hematological malignancies.
Article
Spectroscopy
Francesco D'Amico, Raffaele Graziano, Federica D'Aria, Pasquale Russomanno, Silvia Di Fonzo, Jussara Amato, Bruno Pagano
Summary: Epigenetic modifications of DNA and G-quadruplex structures are closely related and can be studied using UV resonance Raman spectroscopy. This study demonstrates that UVRR spectroscopy can detect spectral changes in G-quadruplex structures and indirectly identify modifications in guanine glycosidic conformations and changes induced by H-bond formation or hydration. These findings support the usefulness of UVRR spectroscopy for studying G-quadruplex structures in biologically relevant conditions.
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
(2023)
Article
Chemistry, Analytical
Francesca Romano, Enza Di Gregorio, Gelsomina Riccardi, Chiara Furlan, Nicola Cavallini, Francesco Savorani, Anna Di Porzio, Stefano De Tito, Antonio Randazzo, Eliana Gianolio, Nunzia Iaccarino
Summary: In this study, the effects of multiple administrations of linear and macrocyclic gadolinium-based contrast agents (GBCAs) on the metabolic pathways in healthy mice were investigated. The results showed that the linear GBCA had a significant impact on organs such as the brain, cerebellum, and liver, while the macrocyclic GBCA had a smaller effect. This study paves the way for the safer use of commercially available GBCAs and the development of new GBCAs with lower toxicity.
Article
Chemistry, Physical
Jussara Amato, Nunzia Iaccarino, Federica D'Aria, Francesco D'Amico, Antonio Randazzo, Concetta Giancola, Attilio Cesaro, Silvia Di Fonzo, Bruno Pagano
Summary: This study investigates the conformational equilibria of sequences forming noncanonical DNA structures in the promoter regions of important oncogenes BCL2 and KRAS, and their dependence on pH and cell-mimicking molecular crowding conditions. The results reveal that the i-motif structures in the promoters of BCL2 and KRAS are highly dynamic and exist in pH-dependent equilibrium with hairpin and hybrid i-motif/hairpin species. The study provides valuable insights into the factors that influence the molecular-level equilibrium between different conformational species involved in oncogene expression.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Thermodynamics
Federica D'Aria, Bruno Pagano, Concetta Giancola
Summary: Cyclodextrins (CDs) have been shown to improve the stability, solubility, and bioavailability of various molecules, with low toxicity for different routes of administration. Isothermal titration calorimetry (ITC) is a key method for studying cyclodextrin/guest interaction, providing important thermodynamic parameters simultaneously.
JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
(2022)