Cataracts, an eye lens clouding disease, are debilitating and while operable, remain without a cure. αA66-80 crystallin peptide abundant in cataracted eye lenses contributes to aggregation of αA-crystallin protein leading to cataracts. Inspired by the versatility of macrocycles and programmable guest selectivity through discrete functionalizations, we report on three water-soluble ionic resorcinarene receptors (A, B, and C) that disrupt the aggregation of αA66-80 crystallin peptide. A and B each possess four anionic sulfonate groups, while C includes four cationic ammonium groups with four flexible extended benzyl groups. Through multiple non-covalent attractions, these receptors successfully disrupt and reverse the aggregation of αA66-80 crystallin peptide, which was studied through spectroscopic, spectrometric, calorimetric, and imaging techniques. The αA66-80·receptor complexes were also explored using molecular dynamics simulation, and binding energies were calculated. Even though each of the three receptors can bind with the peptide, receptor C was characterized by the highest binding energy and affinity for three different domains of the peptide. In effect, the most efficient inhibitor was a cationic receptor Cvia extended aromatic interactions. These results highlight the potential of versatile and tunable functionalized resorcinarenes as potential therapeutics to reverse the aggregation of α-crystallin dominant in eye cataracts.

The binding affinity for pyrophosphate (PPi) in aqueous media by N-alkyl ammonium resorcinarene salts can be enhanced via using weakly coordinating counter anions and modifying the upper rims of the receptors and the lower rim hydroxyl groups.

Resorcinarenes decorated with sulfonate groups are anionic in nature and water soluble with a hydrophobic electron-rich interior cavity. These receptors are shown to bind zwitterionic aromatic mono-N-oxides and cationic di-N-oxide salts with varying spacer lengths. Titration data fit a 1:1 binding isotherm for the mono-N-oxides and 2:1 binding isotherm for the di-N-oxides. The first binding constants for the di-N-oxides (K₁: 10⁴ M⁻¹) are higher compared to the neutral mono-N-oxide (K: 10³ M⁻¹) due to enhanced electrostatic attraction from a receptor with an electron-rich internal cavity and cationic and electron deficient N-oxides. The interaction parameter α reveals positive cooperativity for the di-N-oxide with a four-carbon spacer and negative cooperativity for the di-N-oxides that have spacers with more four carbons. This is attributed to shape complementarity between the host and the guest.