LAUSR

DNA or RNA strands that are composed stretches of guanines (G-tracts) divided by other bases are able to form Gquadruplexes, a tetra-helical structure with stacked G-tetrad planes connected by Hoogsteen hydrogen bonds and stabilized by cations such as Na+ and K+ (Largy et al. 2016; Neidle et al. 2006; Neidle and Parkinson 2003). Interor intramolecular Gquadruplex structures are polymorphic and can form parallel or antiparallel structures based on the orientation of the strands in a G-quadruplex. G-quadruplexes have been revealed in human cells using an antibody and small molecules (Biffi et al. 2013; Hansel-Hertsch et al. 2017; Henderson et al. 2014) and shown to play important roles in numerous processes such as DNA replication, recombination, transcription, translation, and telomere maintenance (Blackburn 2001; Cahoon and Seifert 2009; de Lange 2002; Jiang et al. 2018; Kumari et al. 2007; Lei et al. 2004; Lopes et al. 2011; Paeschke et al. 2011; Siddiqui-Jain et al. 2002). In addition, G-quadruplexes have been implicated in neurological diseases such as amyotrophic lateral sclerosis (ALS), ataxia, and fragile X syndrome (Simone et al. 2015). And the presence of putative sequences forming Gquadruplexes has also been reported in various viral genomes (Metifiot et al. 2014). Therefore, these findings made G-quadruplexes attractive therapeutic targets for anti-disease/virus drug design (HanselHertsch et al. 2017; Neidle 2012; Raffa et al. 2018). To date, thousands of small compounds have been reported to bind with G-quadruplexes through stacking with the terminal Gtetrad layer typified by the structure of the bimolecular human telomeric quadruplex, d[TAGGGTTAGGGT]2, in complex with the anti-cancer drug BRACO-19 (Campbell et al. 2008). However, the inherent structural polymorphism of Gquadruplex implies that a unique G-quadruplex conformation could be recognized by a specific ligand. In this light, knowledge of the precise 3D-structure is important and required to design highly specific ligands capable of discriminating the diverse G-quadruplex topologies/structures.