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.

Spotlight on G-Quadruplexes: From Structure and Modulation to Physiological and Pathological Roles

“…An example of the functional relevance of G-quadruplexes in viral genomes was provided in a reporter assay of PQS-containing human cytomegalovirus (HCMV) regulatory sequences, where chemically induced G-quadruplex stabilization resulted in transcriptional suppression of some of the tested viral promoters [ 200 ], suggesting that these secondary structures can be used as targets for specific antiviral drugs (reviewed in ref. [ 201 , 202 ]). Interestingly, a fraction of the predicted G4-forming sequences from the unicellular eukaryote Saccharomyces cerevisiae was found to be conserved in other fungal species [ 203 ], with these sequences being enriched in promoters, telomeres, rDNA, mtDNA, and sites of frequent double-strand breaks [ 203 , 204 ].…”

Development of a single‐domain antibody to target a G‐quadruplex located on the hepatitis B virus covalently closed circular DNA genome

“…13 In recent years, there have been several studies focused on identifying G4s in the HBV genome and to elucidate their role in the viral life cycle. 14,15 Through a comprehensive biophysical and cell biology approach, our previous research has shown the existence of a highly ordered parallel G-quadruplex (G4) structure in the EnhII/PreC promoter region of the HBV genome and its role in regulating HBV core protein translation. 16 Moreover, researchers have also identified 12 potential quadruplex-forming sequences (PQS), some of which have been attributed to have roles in cccDNA phase separation, as well as regulation of HBsAg and HBcAg production.…”

“…In recent years, there have been several studies focused on identifying G4s in the HBV genome and to elucidate their role in the viral life cycle 14,15 . Through a comprehensive biophysical and cell biology approach, our previous research has shown the existence of a highly ordered parallel G‐quadruplex (G4) structure in the EnhII/PreC promoter region of the HBV genome and its role in regulating HBV core protein translation 16 .…”