Functionalized Resorcinarenes Effectively Disrupt the Aggregation of Alpha A66-80 Crystallin Peptide Related to Cataracts
Published In
Rsc Medicinal Chemistry
Document Type
Citation
Publication Date
11-1-2021
Abstract
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.
Rights
© Royal Society of Chemistry 2021
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DOI
10.1039/d1md00294e
Persistent Identifier
https://pdxscholar.library.pdx.edu/chem_fac/427
Citation Details
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