Genome-mining for Novel G-quadruplex Drug targets

Guanine quadruplexes or G4s are DNA and RNA secondary structures that are formed by breaking the canonical Watson–Crick base-pairing. Two or more planar structures, each formed by four Hoogsteen base-paired guanine nucleotides, constitute the core of G4 structures. Over the last one and a half decades, these structures have been shown to have important ramifications in genomic processes including, replication , transcription , recombination , nucleosome exclusion and DNA methylation. These structures are also known to engage transcription factors, helicases and other nuclear proteins . Studies focusing on the role of G4s in prokaryotes and eukaryotes have shown that these structures are prevalent and conserved in the regulatory regions of both eukaryotes and prokaryotes and have important functional outcomes.

An increasing number of reports providing evidences on the in vivo existence of G4s have brought forth a renewed interest in these structures. G4s are largely formed by specific nucleotide motifs which are also called putative G4 (PG4) motifs. Computationally mined G4 or PG4 motifs are known to associate with promoter regions in the mammalian as well as prokaryotic genomes.

Here we try to mine the organism genome with an integrated approach that predicts and validates novel putative G-quadruplex forming nucleic acid (PG4 motifs) as a drug targets. We first built a classified dataset that integrates a variety of genomic data and further systematically searched for the Novel G-quadruplex- drug targets. We then devised strategies to developed small molecule modulators of these to control the phenomenon associated with these structures.