Multi-approach strategy to probe the interactions between anions and new classes of molecular receptors

The anion distribution across cell membranes is a major element governing biological processes in the human body. This is ensured by ion channels, membrane proteins with the capacity to selectively regulate ion flows. Disruption of these electrophysiological ion transport phenomena can lead to serious pathologies (channelopathies). One example is the deregulation of chloride ion concentration, leading in particular to cystic fibrosis.[1] A new therapeutic strategy for treating channelopathies involves designing molecules that allow ions to be transported across lipid membranes, thereby restoring ionic currents and their physiological functions. [2] In this context, new families of receptors are being developed that combine several low-energy interactions (hydrogen, halogen and pi-anion bonds). A combination of several weak interactions is likely to generate stronger and more selective bonds, thereby modulating existing properties or generating new ones. The aim of the work presented here is to characterize in detail, using a multi-approach experimental strategy, the interaction processes at play between these receptors and a series of target anions. Gas-phase studies can provide valuable information about the interactions established at the molecular level between the anions and the receptors. These will be carried out using mass spectrometry to determine the stoichiometry of the anion/receptor complexes and to obtain structural characterization using tandem mass spectrometry (MSn) to determine the position of the anion on these new structures. This work is complemented by theoretical calculations using DFT (Density Functional Theory). The results obtained in the gas phase are complemented by the characterization of ligand-host complexes in solution [3], by NMR titrations and by UV/vis and fluorescence spectroscopy experiments. References [1] S.M. Rowe et al. N. Engl. J. Med. 2005, 352, 1992-2001. [2] T. Sato et al. J. Biol. Chem. 1998, 273, 21455-21462. [3] R. Plais et al. ChemPhysChem, 2022, e202200524