Functionalized Resorcinarenes Effectively Disrupt the Aggregation of Alpha A66-80 Crystallin Peptide Related to Cataracts
Rsc Medicinal Chemistry
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 C via 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.
© Royal Society of Chemistry 2021
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Twum, K., Bhattacharjee, A., Laryea, E. T., Esposto, J., Omolloh, G., Mortensen, S., Jaradi, M., Stock, N. L., Schileru, N., Elias, B., Pszenica, E., McCormick, T. M., Martic, S., & Beyeh, N. K. (2021). Functionalized resorcinarenes effectively disrupt the aggregation of αA66-80 crystallin peptide related to cataracts. RSC Medicinal Chemistry, 10.1039.D1MD00294E. https://doi.org/10.1039/d1md00294e