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Information × Registration Number 0219U000888, 0118U002266 , R & D reports Title Development of highly-efficient agent for prevention of pathological aggregation of proteins in neurodegenerative diseases and amyloidoses popup.stage_title Head Kovalska Vladyslava Borysivna, Доктор біологічних наук Registration Date 13-03-2019 Organization Institute of Molecular Biology and Genetics of NASU popup.description2 The study of amyloid fibrils and their fibrillization kinetics, as well as development of the tools to influence this process (both to avoid the formation of pathological fibrils and to develop artificial functional materials on their basis) is an actual task. During performing the project, influence of series of porphyrines with modifications in the macrocycle periphery on the formation of insulin fibrils was studied. The influence on the fibrillization kinetics was estimated using the fluorescent assay based on the amyloid-sensitive dye. According to the results of the fluorescent studies, tetraphenylporphyrins demonstrated higher inhibitory activity as compared to octaethylporphyrins. Tetraphenylporphyrin without central metal atom and containing carboxy groups demonstrated high inhibitory activity (90%), while this of tetraphenylporphyrin with carboxygroups and coordinated palladium atom was only 60%. The obtained results allowed to make a conclusion about the negative influence of the central metal atom on the inhibitory activity. It was shown that the inhibitory activity of porphyrins practically does not depend on the number of introduced N-substituents, since porphyrins containing 1 and 4 substituents demonstrated similar inhibitory activity. Using the method of scanning electron microscopy, we studied the morphology of the products of insulin amyloid aggregation reaction in the presence of porphyrins of different chemical structure. In the presence of porphyrins, amyloid fibrils with certain differences in morphology are formed depending on the peripheral substituents and central metal atom. In the presence of tetraphenylporphyrins containing peripheral substituents, longer fibrils are formed with lesser tendency to lateral aggregation as compared to free insulin. In the presence of metal-free tetraphenylporphyrin TPP, more elongated fibrils are formed as compared to the presence of Mn- and Pd-containing tetraphenylporphyrins, though their inhibitory activities are similar. Hence, central metal atom and peripheral modifications influence the morphology of the products. To determine the ability of porphyrins to destroy amyloid fibrils, two porphyrins with different peripheral substituents were incubated with previously formed insulin fibrils. Using the method of scanning electron microscopy, the presence of formed fibrils with branched morphology was confirmed, which are similar to the fibrils of free insulin. From the obtained results it could be concluded that the presence of the studied compounds leads to some shortening of the insulin fibrils, but does not lead to their significant destruction during incubation. Summarizing, peripheral modifications of porphyrin macrocycle influence the intensity of inhibition of fibrillization reaction and aggregates morphology depending on the chemical structure of the substituents. The obtained results are important for the designing of the anti-fibrillogenic agents with required properties basing on these metallocomplexes. Product Description popup.authors Лосицький Михайло Юрійович Ярмолюк Сергій Миколайович popup.nrat_date 2020-04-02 Close