Abstract
G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key cellular processes, such as transcription and replication. Since their discovery, G4s have been mainly investigated for their role in cancer and as targets in anticancer therapy. More recently, exploration of the presence and role of G4s in viral genomes has led to the discovery of G4-regulated key viral pathways. In this context, employment of selective G4 ligands has helped to understand the complexity of G4-mediated mechanisms in the viral life cycle, and highlighted the possibility to target viral G4s as an emerging antiviral approach. Research in this field is growing at a fast pace, providing increasing evidence of the antiviral activity of old and new G4 ligands. This review aims to provide a punctual update on the literature on G4 ligands exploited in virology. Different classes of G4 binders are described, with emphasis on possible antiviral applications in emerging diseases, such as the current COVID-19 pandemic. Strengths and weaknesses of G4 targeting in viruses are discussed.
Highlights
G-quadruplexes (G4s) are noncanonical arrangements that occur in guanine (G)rich DNA and RNA strands during key cellular processes
We focus on the G4 ligands employed as antiviral agents, aiming to provide a comprehensive update covering the available literature, with major focus on the last three years
Compound 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphyrin (TMPyP4, Figure 2) is one of the most extensively studied G4-binding molecules, because its physicochemical features, such as size, planar core, positively charged substituents, and hydrophobicity, make it fit to stack on the G4 scaffold
Summary
G-quadruplexes (G4s) are noncanonical arrangements that occur in guanine (G)rich DNA and RNA strands during key cellular processes. G4s in cancer has unraveled many biological pathways, providing new insights on the role of G4s in cancer pathogenesis, and corroborating the possibility to target these structures for therapy [4] This evidence prompted investigation of G4s in different organisms, such as yeasts [6], bacteria [7,8], and viruses [9], where G4s emerged as important elements in the regulation of these microorganisms’ biological processes. The development and optimization of bioinformatics tools to detect G4 motifs have highly accelerated the identification of viral PQSs; interestingly, most of the identified sequences were proved to fold into G4s in vitro [16] In this context, employment of known G4 ligands provided an excellent tool to unravel G4mediated viral pathways, eventually proving that G4 targeting can be a promising and innovative approach in antiviral therapy [17]. Human viruses have been considered, with a final analysis that includes the recent advances against the SARS-CoV-2 virus
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