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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).

References associated with 2.B.41 family:

Chen, Y. and D. Yang. (2012). Sequence, stability, and structure of G-quadruplexes and their interactions with drugs. Curr Protoc Nucleic Acid Chem Chapter17: Unit17.5. 22956454
Kaucher, M.S., W.A. Harrell, Jr, and J.T. Davis. (2006). A unimolecular G-quadruplex that functions as a synthetic transmembrane Na+ transporter. J. Am. Chem. Soc. 128: 38-39. 16390110
Li, C., H. Chen, Q. Chen, H. Shi, X. Yang, K. Wang, and J. Liu. (2020). Lipophilic G-Quadruplex Isomers as Biomimetic Ion Channels for Conformation-Dependent Selective Transmembrane Transport. Anal Chem. [Epub: Ahead of Print] 32564593