Manipulating DNA G‐Quadruplex Structures by Using Guanosine Analogues

The ability to control the folding topology of DNA G‐quadruplexes allows for rational design of quadruplex‐based scaffolds for potential use in various therapeutic and technological applications. By exploiting the distinct conformational properties of some base‐ and sugar‐modified guanosine surrogates, conformational transitions can be induced through their judicious incorporation at specific sites in the quadruplex core. Changes may involve tetrad polarity inversions with conservation of the global fold or complete refolding to new topologies. Reliable predictions relating to low‐energy conformers formed upon specific chemical perturbations of the system and the rational design of modified sequences suffer from our still limited understanding of the subtle interplay of various favorable and unfavorable interactions within a particular quadruplex scaffold. However, aided by an increasing number of systematic substitution experiments and high‐resolution structures of modified quadruplex variants, critical interactions, in addition to glycosidic bond angle propensities, are starting to emerge as important contributors to modification‐driven quadruplex refolding. Enforcing conformation changes: Incorporation of guanosine analogues with specific conformational and steric features into selected positions in DNA quadruplexes affords the possibility of enforcing conformation changes, ultimately allowing the rational design of tailor‐made architectures for a variety of quadruplex‐based applications.