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

Yury A. Gubarev; Natalya Sh. Lebedeva; Elena S. Yurina; Sergey A. Syrbu; Aleksey N. Kiselev; Mikhail A. Lebedev

doi:10.1016/j.jpha.2021.08.003

Volume 11 Issue 6

Dec. 2021

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Article Navigation > Journal of Pharmaceutical Analysis > 2021 > 11(6): 691-698

Yury A. Gubarev, Natalya Sh. Lebedeva, Elena S. Yurina, Sergey A. Syrbu, Aleksey N. Kiselev, Mikhail A. Lebedev. Possible therapeutic targets and promising drugs based on unsymmetrical hetaryl-substituted porphyrins to combat SARS-CoV-2[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 691-698. doi: 10.1016/j.jpha.2021.08.003

Citation:

Yury A. Gubarev, Natalya Sh. Lebedeva, Elena S. Yurina, Sergey A. Syrbu, Aleksey N. Kiselev, Mikhail A. Lebedev. Possible therapeutic targets and promising drugs based on unsymmetrical hetaryl-substituted porphyrins to combat SARS-CoV-2[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 691-698. doi: 10.1016/j.jpha.2021.08.003

Citation:

Yury A. Gubarev, Natalya Sh. Lebedeva, Elena S. Yurina, Sergey A. Syrbu, Aleksey N. Kiselev, Mikhail A. Lebedev. Possible therapeutic targets and promising drugs based on unsymmetrical hetaryl-substituted porphyrins to combat SARS-CoV-2[J]. Journal of Pharmaceutical Analysis, 2021, 11(6): 691-698. doi: 10.1016/j.jpha.2021.08.003

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

doi: 10.1016/j.jpha.2021.08.003

a. G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 153045, Ivanovo, Russia;
b. Ivanovo State University of Chemistry and Technology, 153000, Ivanovo, Russia

Funds:

The reported study was funded by RFBR (Project No.: 20-04-60067).

Received Date: May 12, 2021
Accepted Date: Aug. 03, 2021
Rev Recd Date: Jul. 15, 2021
Available Online: Jan. 12, 2022
Publish Date: Dec. 15, 2021

Abstract

Abstract

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 ¹O₂, 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.
- Porphyrins,
- SARS-CoV-2,
- Molecular docking,
- Photoinactivation

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References(41)

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