Posted by 7-ketocholesterol (7-oxocholesterol, 7-KC) is the major oxidation product of cholesterol (CHOL), and one of the most toxic metabolites formed when an active oxygen radical reacts with cholesterol. 7-KC is associated with several diseases, like cardiovascular diseases, age-related macular degeneration, and Alzheimer’s disease. 7-KC can be found in high amount in human atherosclerotic plaque.
It is well-known that several cyclodextrins (CDs) have cholesterol binding affinity. Thus came the idea to specifically modify CDs in order to selectively bind 7-KC.
A custom-tailored cyclodextrin dimer was designed to specifically bind 7-KC. Several studies were preformed to better understand the complex of CD and 7-KC.
The combined results of these experiments demonstrate that the CD dimer has ~1000 fold stronger affinity for 7-KC than for CHOL. The binding constants obtained from the in vitro methods compare well with those obtained from metadynamics simulations, and they are comparable or even higher than other values reported in literature for similar systems of steroid complexes with CD dimers.
The fact that cyclodextrin dimers can differentiate CHOL and the toxic 7-KC, that only differs from an oxo group is outstanding and opens the way to rationally design other CD derivatives that can selectively bind toxic metabolites of different molecules.
The recent results in synthesis, characterization and scaling up to kg-scale manufacturing for clinical trials were presented at EuroCD_2023.
Referencea
Ghazaiel et al. 7-Ketocholesterol: Effects on viral infections and hypothetical contribution in COVID-19. The Journal of Steroid Biochemistry and Molecular Biology 212, 2021, 105939.
doi: 10.1016/j.jsbmb.2021.105939
Sadrerafi, K. et al. Manufacturing dimerized cyclodextrins for reversal of cardiovascular disease. 7th European Cyclodextrin Conference, Sep.5-8, 2023, Budapest, O-04