Possible therapeutic targets and promising drugs based on unsymmetrical hetaryl-substituted porphyrins to combat SARS-CoV-2.

Autor: Gubarev YA; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia., Lebedeva NS; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia., Yurina ES; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia., Syrbu SA; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia., Kiselev AN; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia.; Ivanovo State University of Chemistry and Technology, 153000, Ivanovo, Russia., Lebedev MA; G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia.; Ivanovo State University of Chemistry and Technology, 153000, Ivanovo, Russia.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical analysis [J Pharm Anal] 2021 Dec; Vol. 11 (6), pp. 691-698. Date of Electronic Publication: 2021 Aug 05.
DOI: 10.1016/j.jpha.2021.08.003
Abstrakt: Coronavirus disease 2019 is a serious disease that causes acute respiratory syndrome and negatively affects the central nervous system. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crosses the blood-brain barrier due to the spike (S) protein on the surface of the viral particles. Thus, it is important to develop compounds that not only have an inhibitory effect but are also capable of completely deactivating the S protein function. This study describes the purposeful modification of porphyrins and proposes compounds, asymmetrically hetaryl-substituted porphyrins with benzothiazole, benzoxazole, and N-methylbenzimidazole residues, to deactivate the S protein functions. Molecular docking of SARS-CoV-2 proteins with hetaryl-substituted porphyrins showed that the viral S protein, nucleocapsid (N) protein, and non-structural protein 13 (nsp13) exhibited the highest binding affinity. Hetaryl-substituted porphyrins form strong complexes (13-14 kcal/mol) with the receptor-binding domain of the S protein, while the distance from the porphyrins to the receptor-binding motif (RBM) does not exceed 20 Å; therefore, RBM can be oxidized by 1 O 2 , which is generated by porphyrin. Hetaryl-substituted porphyrins interact with the N protein in the serine/arginine-rich region, and a number of vulnerable amino acid residues are located in the photooxidation zone. This damage complicates the packaging of viral RNA into new virions. High-energy binding of hetaryl-substituted porphyrins with the N- and C-terminal domains of nsp13 was observed. This binding blocks the action of nsp13 as an enzyme of exoribonuclease and methyltransferase, thereby preventing RNA replication and processing. A procedure for the synthesis of hetaryl-substituted porphyrins was developed, new compounds were obtained, their structures were identified, and their photocatalytic properties were studied.
Competing Interests: The authors declare that there are no conflicts of interest.
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Databáze: MEDLINE
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