Investigation of G-quadruplex forming motifs as potential therapeutic targets in human-infecting pathogens

Abstract

G-quadruplex structures, often abbreviated as G4s, are distinctive non-canonical secondary structures. These structures form in guanine-rich nucleic acid sequences, including both DNA and RNA. G-tetrads, which are the building blocks of G4s, arise through the association of four guanines in a cyclic Hoogsteen-hydrogen bond base pairing. At least two or more planar G-tetrads are stacked on top of each other to form G4s and stabilized by monovalent cations such as potassium or sodium[1]. G4s display topological polymorphism, based on the involvement of a single strand (intramolecular) or multiple strands (intramolecular)[2]. G4s also exhibit varied topologies depending on the polarity of the strands participating in the structure formation: parallel, antiparallel, or hybrid. The distribution of G4s is non-random in the genome[3]. These structures are more prevalent in telomeres, gene promoters, replication origins, 5’ and 3’ UTRs, and introns, and therefore play significant roles in gene regulation. Based on their distribution and unique structural and functional features, G4s have garnered attention as attractive therapeutic targets in diseases such as cancer and neurological disorders. Apart from their functional relevance in the eukaryotic genome, G4s also serve as critical regulatory elements in the prokaryotic genome that influence pathogenicity, stress adaptation, and gene expression, making them important targets for therapeutic intervention[4].