Why to target G‐quadruplexes using peptides: Next‐generation G4‐interacting ligands

Abstract

Guanine‐rich oligonucleotides existing in both DNA and RNA are able to fold into four‐stranded DNA secondary structures via Hoogsteen type hydrogen‐bonding, where four guanines self‐assemble into a square planar arrangement, which, when stacked upon each other, results in the formation of higher‐order structures called G‐quadruplexes. Their distribution is not random; they are more frequently present at telomeres, proto‐oncogenic promoters, introns, 5′‐ and 3′‐untranslated regions, stem cell markers, ribosome binding sites and so forth and are associated with various biological functions, all of which play a pivotal role in various incurable diseases like cancer and cellular ageing. Several studies have suggested that G‐quadruplexes could not regulate biological processes by themselves; instead, various proteins take part in this regulation and can be important therapeutic targets. There are certain limitations in using whole G4‐protein for therapeutics purpose because of its high manufacturing cost, laborious structure prediction, dynamic nature, unavailability for oral administration due to its degradation in the gut and inefficient penetration to reach the target site because of the large size. Hence, biologically active peptides can be the potential candidates for therapeutic intervention instead of the whole G4‐protein complex. In this review, we aimed to clarify the biological roles of G4s, how we can identify them throughout the genome via bioinformatics, the proteins interacting with G4s and how G4‐interacting peptide molecules may be the potential next‐generation ligands for targeting the G4 motifs located in biologically important regions.