Cataract disease remains without a cure and is caused by the clouding of the eye lens. The onset of lens clouding is due to aging, protein post-translational modifications, and damage by radicals such as reactive oxygen species generated by exogenous and endogenous factors.1 The αA-crystallin, a heat-shock protein, maintains the solubility and stability of lens proteins and lens clarity by preventing protein aggregation, which may lead to lens clouding and eventually cataracts. In particular, the αA66-80 peptide fragment of αA-crystallin, among others, was observed at a high level in cataracts eye lenses. Herein, we use three different ionic resorcinarene macrocycles to study how they affect αA 66-80 peptide aggregation. Two of the receptors are decorated with anionic sulfonate groups, one at the upper and the second at the lower rim. In comparison, the third receptor is a resorcinarene salt that possesses an extended cavity with four ammonium groups at the upper rim and four hydroxyl groups at the lower rim. All the receptors possess hydrophobic internal cavities. The effect of the receptors on the aggregation/de-aggregation of αA66−80 peptide are investigated at the macroscopic level through Fluorescence Aggregation Assay, Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and Mass Spectrometry. Interactions at the molecular level between the receptors and the individual amino acids are investigated qualitatively via NMR spectroscopy and quantitatively via Isothermal Titration Calorimetry (ITC). The experimental results are also supported by DFT computational calculations and molecular docking studies.

Resorcinarene macrocycles effectively disrupt the aggregation of αA66−80 peptide related to cataracts

ACS Spring 2022

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