G-quadruplexes and their ligands

Santos, Tiago; Salgado, Gilmar F.; Cabrita, Eurico J.; Cruz, Carla

http://hdl.handle.net/10362/124890

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Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural-and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.

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Funding Information: (PD/00065/2013). This work was supported by PESSOA program ref. 5079 and project “Projeto de Investigação Exploratória” ref. IF/00959/2015 entitled “NCL targeting by G-quadruplex aptamers for cervical cancer therapy” financed by Fundo Social Europeu e Programa Operacional Potencial Humano. Thanks are due to FCT/MCT for the financial support of the CICS-UBI UIDB/00709/2020 research unit and to the Portuguese NMR Network (ROTEIRO/0031/2013-PINFRA/22161/2016), through national funds and, where applicable, supported by European Investment Funds FEDER through COMPETE 2020, POCI, PORL and PIDDAC.