Roberta Rocca1, Federica Moraca1, Giosuè Costa2, Matteo Nadai3, Matteo Scalabrin3, Carmine Talarico1, Simona Distinto4, Elias Maccioni4, Francesco Ortuso1, Anna Artese1, Stefano Alcaro5, Sara N Richter3. 1. Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", viale Europa, 88100, Catanzaro, Italy. 2. Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", viale Europa, 88100, Catanzaro, Italy. Electronic address: gcosta@unicz.it. 3. Department of Molecular Medicine, University of Padua, via Gabelli 63, 35121, Padua, Italy. 4. Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, via Ospedale 72, Cagliari 09124, Italy. 5. Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro, Campus "Salvatore Venuta", viale Europa, 88100, Catanzaro, Italy. Electronic address: alcaro@unicz.it.
Abstract
BACKGROUND: Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. METHODS: Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. RESULTS: Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. CONCLUSIONS: Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. GENERAL SIGNIFICANCE: The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
BACKGROUND: Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. METHODS: Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. RESULTS: Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. CONCLUSIONS: Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. GENERAL SIGNIFICANCE: The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
Authors: Katia Grillone; Caterina Riillo; Francesca Scionti; Roberta Rocca; Giuseppe Tradigo; Pietro Hiram Guzzi; Stefano Alcaro; Maria Teresa Di Martino; Pierosandro Tagliaferri; Pierfrancesco Tassone Journal: J Exp Clin Cancer Res Date: 2020-06-20
Authors: Yang Mei; Zhong Deng; Olga Vladimirova; Nitish Gulve; F Brad Johnson; William C Drosopoulos; Carl L Schildkraut; Paul M Lieberman Journal: Sci Rep Date: 2021-02-10 Impact factor: 4.996