Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane DerivativeIn VitroandIn Silico
| Autor: | Marina Pavlovna Finogenova, Tatiana Vladimirovna Grebennikova, Tatiana Anatol'evna Timofeeva, Alexander Aleksandrovich Lashkov, Galina K. Sadykova, Artyom Irorevich Odnovorov, Marina Mikhailovna Zhuravleva, Sergey Vadimovich Rubinsky, Svetlana Nikolaevna Norkina, T. M. Garaev, Alexei Gennadievich Prilipov |
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| Rok vydání: | 2020 |
| Předmět: |
Hemagglutination
Mutant Pharmaceutical Science RM1-950 02 engineering and technology medicine.disease_cause 030226 pharmacology & pharmacy influenza virus Virus reverse genetics 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Influenza A virus medicine General Pharmacology Toxicology and Pharmaceutics POPC drug resistance biology molecular docking 021001 nanoscience & nanotechnology antiviral Molecular biology In vitro chemistry M2 proton channel Mechanism of action biology.protein Therapeutics. Pharmacology medicine.symptom m2 proton channel 0210 nano-technology |
| Zdroj: | Advanced Pharmaceutical Bulletin, Vol 11, Iss 4, Pp 700-711 (2021) |
| ISSN: | 2251-7308 2228-5881 |
| Popis: | Purpose: The aminoadamantane derivative of L-histidyl-1-adamantayl ethylamine hydrochloride (HCl*H-His-Rim) has showed a high inhibition level against influenza A virus strains in vitro. The aim of this work is to search and establish evidence of the direct effect of the drug on influenza A virus proton channel M2. Methods: The compound HCl*H-His-Rim was obtained by classical peptide synthesis methods. Influenza A virus mutants of A/PuertoRico/8/34(H1N1) strain were obtained by reverse genetics methods. The mutant samples of the virus were cultured on chicken embryos with a virus titer in the hemagglutination test. ELISA was carried out on Madin-Darby canine kidney (MDCK) monolayer cells when multiplying the virus 10-4-10-6. The binding stability of HCl*H-His-Rim was compared to those of M2 (S31N) and M2 (S31N_A30T) channels by molecular dynamic (MD) modeling. The calculation was performed taking into account the interaction with the model lipid bilayer (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) in the presence of water molecules in accordance with the three-center model. Results: It was found that HCl*H-His-Rim is a direct action drug against influenza A. The most likely conformation of drug binding to target protein has been shown. It has been found that the A30T mutation reduces the binding energy of the drug, and the results obtained in vitro have confirmed the data calculated in silico. Conclusion: The mechanism of action of HCl*H-His-Rim is directly related to the suppression of the function of the proton channel M2 of influenza A virus. |
| Databáze: | OpenAIRE |
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