2.B.41.  The Synthetic G-Quadruplex Ion Transporter (GQ-IT) Family 

Kaucher et al. 2006 described the covalent post-modification of a hydrogen-bonded assembly with the subsequent formation of a potent transmembrane Na⁺ transporter. Olefin metathesis was used to cross-link all 16 guanosine subunits in a lipophilic G-quadruplex. The resulting unimolecular G-quadruplex folds in the environment of a phospholipid membrane and functions as a Na⁺ transporter as judged by fluorescence and ²³Na⁺ NMR transport assays. 

DNA G-quadruplexes are four-stranded globular nucleic acid secondary structures formed in specific G-rich sequences with biological significance, such as human telomeres and oncogene promoters. Chen and Yang 2012 focused on the unimolecular DNA G-quadruplexes, which readily form in solution under physiological conditions and are the most biologically relevant. Available structural data show a great conformational diversity of unimolecular G-quadruplexes that are amenable to small-molecule drug targeting. The relationships between sequence, structure, and stability of unimolecular DNA G-quadruplexes, as well as the recent progress on interactions with small-molecule compounds and insights into rational design of G-quadruplex-interactive molecules has been reviewed (Chen and Yang 2012).

Transport selectivity is a challenge in the design of biomimetic transmembrane channels. Specific ion-dependent lipophilic G-quadruplexes displaying different conformations were designed for the construction of highly selective artificial transmembrane channels (Li et al. 2020). The presence of Pb²⁺ or K⁺ ions prompted the folding of the lipophilic PS2.M sequence into G-quadruplexes with antiparallel and parallel conformations. Membrane immobilization of the G-quadruplex channels restricted the reversible configurational changes between different topologies. 8-Hydroxypyrene-1,3,6-trisulfonic acid (HPTS) transport assays revealed that Pb²⁺-stabilized antiparallel isomers and K⁺-stabilized parallel isomers exhibited significant differences in transmembrane transport. The former showed high Pb²⁺ transport activity (EC50 = 1.55 muM) and selectivity (Pb²⁺/K⁺ selectivity = 30.6), while the latter demonstrated high K⁺ transport activity (EC50 = 0.56 muM) and selectivity (K⁺/Pb²⁺ selectivity = 31.8). The results provided a platform for effective development of conformation-dependent ion-selective biomimetic transmembrane channels. G-quadruplex channels have potential for application in the fields of molecular diagnostics, logic biocomputing, selective separation, and single-molecule biosensing (Li et al. 2020).