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2.B.95.  The Halogen-bonding Mobile Anion Transporter (H-MAT) Family 

Selective transmembrane transport of chloride over competing proton or hydroxide transport is key for the therapeutic application of anionophores. Current approaches rely on enhancing chloride anion encapsulation within synthetic anionophores. However, Johnson et al. 2023 reported the first example of a halogen bonding ion relay in which transport is facilitated by the exchange of ions between lipid-anchored receptors on opposite sides of the membrane. The system exhibits non-protonophoric chloride selectivity, uniquely arising from the lower kinetic barrier to chloride exchange between transporters within the membrane, compared to hydroxide, with selectivity maintained across membranes with different hydrophobic thicknesses. For a range of mobile carriers with known high chloride over hydroxide/proton selectivity, the discrimination is strongly dependent on membrane thickness. Thus, the selectivity of non-protonophoric mobile carriers does not arise from ion binding discrimination at the interface, but rather from a kinetic bias in transport rates, arising from differing membrane translocation rates of the anion-transporter complexes (Johnson et al. 2023).

New mechanisms of ion transport are based on membrane-anchored carriers. These abiotic anchored carriers can be subdivided into two classes: unimolecularand relay transporters. In the former, an individual ion carrier is tethered to a membrane anchoring unit with a sufficiently long linker such that it is capable of reaching across the bilayer and mediating ion transport via a carrier-like mechanism. Examples include molecular ion fishers (Li et al. 2020), swing transporters (Ren et al. 2019), and rotaxane-based shuttles (Wang et al. 2021). In contrast, relay transport, as originally demonstrated by McNally et al. 2008 requires two anchored ion receptors in opposite leaflets of the bilayer to facilitate the exchange of the ion across the membrane interior. Johnson et al. 2023 developed a relay transport system in which the activity is regulated by photo-isomerisation of the transporters within the membrane. Anchoring an ion carrier as part of a phospholipid is advantageous because it provides an amphiphilic transport system which enables enhanced formulation and delivery in future therapeutic applications, unlike typical lipophilic mobile ion carriers. Johnson et al. 2023 showed that this system is two orders of magnitude more active than the previous highest performing relay transporter, with significant selectivity for Cl > OH.

References associated with 2.B.95 family:

Johnson, T.G., A. Docker, A. Sadeghi-Kelishadi, and M.J. Langton. (2023). Halogen bonding relay and mobile anion transporters with kinetically controlled chloride selectivity. Chem Sci 14: 5006-5013. 37206385
Li, N., F. Chen, J. Shen, H. Zhang, T. Wang, R. Ye, T. Li, T.P. Loh, Y.Y. Yang, and H. Zeng. (2020). Buckyball-Based Spherical Display of Crown Ethers for Custom Design of Ion Transport Selectivity. J. Am. Chem. Soc. 142: 21082-21090. 33274928
McNally, B.A., E.J. O''Neil, A. Nguyen, and B.D. Smith. (2008). Membrane transporters for anions that use a relay mechanism. J. Am. Chem. Soc. 130: 17274-17275. 19035637
Ren, C., F. Chen, R. Ye, Y.S. Ong, H. Lu, S.S. Lee, J.Y. Ying, and H. Zeng. (2019). Molecular Swings as Highly Active Ion Transporters. Angew Chem Int Ed Engl 58: 8034-8038. 30983075
Wang, C., S. Wang, H. Yang, Y. Xiang, X. Wang, C. Bao, L. Zhu, H. Tian, and D.H. Qu. (2021). A Light-Operated Molecular Cable Car for Gated Ion Transport. Angew Chem Int Ed Engl 60: 14836-14840. 33843130