G-Quadruplexes in the Viral Genome: Unlocking Targets for Therapeutic Interventions and Antiviral Strategies

Abstract

G-quadruplexes (G4s) are unique non-canonical four-stranded nucleic acid secondary structures formed by guanine-rich DNA or RNA sequences. Sequences with the potential to form quadruplex motifs (pG4s) are prevalent throughout the genomes of all organisms, spanning from prokaryotes to eukaryotes, and are enriched within regions of biological significance. In the past few years, the identification of pG4s within most of the Baltimore group viruses has attracted increasing attention due to their occurrence in regulatory regions of the genome and the subsequent implications for regulating critical stages of viral life cycles. In this context, the employment of specific G4 ligands has aided in comprehending the intricate G4-mediated regulatory mechanisms in the viral life cycle, showcasing the potential of targeting viral G4s as a novel antiviral strategy. This review offers a thorough update on the literature concerning G4s in viruses, including their identification and functional significance across most of the human-infecting viruses. Furthermore, it delves into potential therapeutic avenues targeting G4s, encompassing various G4-binding ligands, G4-interacting proteins, and oligonucleotide-based strategies. Finally, the article highlights both progress and challenges in the field, providing valuable insights into leveraging this unusual nucleic acid structure for therapeutic purposes.

Keywords: G-quadruplex; G-quadruplex forming sequences; G-quadruplex ligands; G4-interacting proteins; antiviral activity; non-canonical G4s; oligonucleotides; small-molecule drugs; targeting G4s; virus.

Figure 1

Building blocks and structures of the G-quadruplex (G4) and its various topologies. (A) Chemical structure of four guanines linked together through eight Hoogsteen hydrogen bonds (left panel) and a schematic illustration of a planar guanine tetrad (middle panel) as well as a G-quadruplex stabilized with monovalent cations (M⁺) (right panel). Red arrows in the backbone denote 5′-to-3′ strand direction; (B) schematic representation showing different topologies of intermolecular (left panel) and intramolecular G4 structures (right panel); (C) the conventional nucleotide sequences capable of forming a G-quadruplex structure, where “N” represents the loop sequences (created with BioRender.com).

Figure 2

Schematic representation summarizing the presence and functional relevance of G-quadruplexes in viruses. Each virus is depicted with its virion structure, genome organization, genome size, a schematic representation of G4 locations in the viral genome, and the functional roles of G4s in the viruses (created with BioRender.com).

Figure 3

Chemical structures of G4 binding ligands demonstrating antiviral properties. (A) TMPyP4; (B) BRACO-19 (B19); (C) Phen-DC3; (D) Pyridostatin (PDS); (E) PDP; (F) N-methyl mesoporphyrin IX (NMM).