Antiamyloid fullerenes
"Soccer ball" against Alzheimer's disease
Natalia Bykova, ITEB RAS Press Service
A group of researchers from the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences has discovered a new property of fullerene C60, which will help in the treatment of Alzheimer's disease. The compound binds to the most toxic protein and prevents the formation of amyloid aggregates in vitro. The results of the work are presented in the journal Colloids and surfaces B: Biointerfaces (Bobylev et al., Anti-amyloid activities of three different types of water-soluble fullerene derivatives).
Amyloidosis is a group of incurable diseases. Their main feature is the formation and accumulation of amyloid aggregates in various organs and tissues. All these deposits consist of proteins or their fragments – peptides. These proteins and peptides do not form under normal conditions or perform some important function unrelated to pathologies. But it happens that for reasons that have not yet been clarified, they begin to behave nontrivially, in particular, they form incorrect structures – amyloid aggregates. These deposits have a toxic effect on the surrounding cells of the body, causing their death. In each disease, different proteins precede the formation of amyloids. In Alzheimer's disease, pathological processes occur in the brain, where a large number of amyloid beta peptides are synthesized – A-beta peptides (1-40) and (1-42).
These peptides begin to stick together, forming amyloid plaques – the largest deposits. Intermediate forms of aggregates of these peptides, or, in scientific terms, oligomers actually destroy brain cells. In the patient, this manifests itself in a gradual decrease in memory and mental performance until the complete disintegration of the personality.
Researchers have been trying for a long time to find an opportunity to influence the process of formation and accumulation of amyloid aggregates.
A group of scientists from the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, together with colleagues from the Institute of Problems of Chemical Physics of the Russian Academy of Sciences, chose a strategy aimed at reducing the degree of toxicity of certain amyloids for brain cells. The target was fragment 1-42 – A-beta (1-42), a peptide that is formed in Alzheimer's disease and, according to the results of many studies, is the most dangerous.
Alexander Bobylev, the first author of the article, Senior researcher at ITEB RAS, comments: "We screened a large number of different compounds, but C60 fullerene derivatives proved to be the most effective.It is a unique compound by its nature, consisting of carbon atoms. Its molecule resembles a football in shape, since it is a sphere in which pentagonal and hexagonal polyhedra constructed from carbon atoms are included. We chose this compound because it is able to bind in vitro to A-beta (1-42) peptides and prevent further aggregation of the latter."
The main problem faced by scientists in the study of this fullerene was its low solubility for biomedical purposes. But with the participation of colleagues from the Institute of Problems of Chemical Physics of the Russian Academy of Sciences, researchers still managed to obtain 3 derivatives of fullerene C60, called compounds 1, 2 and 3, respectively, which had very high solubility, extremely low toxicity and a strong antiamyloid effect. Invitro studies have shown the ability of new fullerene derivatives to interfere with the aggregation of Abeta (1-42)-peptide. They bound to the peptide and prevented it from forming mature amyloid fibrils similar to those found in amyloid deposits in the brains of Alzheimer's patients.
In experiments on rat brain cells, it was shown that all three studied derivatives of fullerene C60 inhibit the toxicity of the most dangerous intermediates of aggregation of A-beta (1-42)-peptide oligomers.
Figure from the article Bobylev et al. – VM.
At the same time, they themselves are practically harmless. Compound 3, which scientists recognized as the most promising, turned out to be 4 times less toxic than the usual aspirin.
"Of course, this study is just the beginning of a long journey of testing new compounds as candidates for the role of drugs for the treatment of Alzheimer's disease. And the disease itself is very complex, not fully studied and has a number of other pathological signs, which should also be paid attention to when developing therapeutic agents. But now the results we have obtained allow us to hope that these compounds will find application in the therapy of amyloidosis, and, in particular, Alzheimer's disease," notes Alexander Bobylev.
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