N-ACYL AMINO ACID DERIVATIVES OF 2-NORBORNANACETIC ACID, CAPABLE INHIBIT VIRUSES OF INFLUENZA A STRAIN RESISTANT TO ADAMANTAN DRUGS

DOI: https://doi.org/10.29296/25877313-2018-01-07
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1
Year: 
2018

V.A. Shibnev Dr.Sc. (Chem..), Professor, Leading Researcher, Laboratory of Ontogenesis Viruses, N.F. Gamaleya FRCEM Russian Ministry of Health (Moscow) E-mail: shibnev@yandex.ru T.M. Garaev Ph.D., Senior Researcher, Laboratory of Ontogenesis Viruses, N.F. Gamaleya FRCEM Russian Ministry of Health (Moscow) E-mail: gtim@fmradio.ru M.P. Finogenova Ph.D., Leading Researcher, Laboratory of Ontogenesis Viruses, N.F. Gamaleya FRCEM Russian Ministry of Health (Moscow) E-mail: fimapa@yndex.ru P.G. Deryabin Dr.Sc. (Med.), Professor, Deputy Director for Scientific Work, Ivanovsky Institute of Virology, N.F. Gamaleya FRCEM Russian Ministry of Health (Moscow) E-mail: pg_deryabin@mail.ru

Viroporin M2 is vital to the influenza virus for infection of the cell. It is an ion channel built into the viral envelope that selective-ly conducts protons from the cell through the interior of the virus. At a certain acidity value of the medium, the protein M2 is activated and begins to pump protons, lowering the pH inside the virus particle and thereby causing its decay. Thus, the genetic material of the virus is released into the cytoplasm of the host cell. Channel M2 is the target on which the action of preparations of the adamantane (rimantadine and amantadine) is directed. In recent years, due to the mutational substitution of serine at position 31 for asparagine (S31N) in the M2 channel protein, circulating influenza viruses have become resistant to adamantane drugs and their use for treat-ment and prevention is ineffective. There are all reasons to believe that synthetic derivatives of 2-norbornane acetic acid with amino acid residues and peptides can claim a model for the creation of new antiviral drugs as structural analogues of aminoadamantanes. Synthesized compounds have anti-influenza activity and act on strains of influenza A virus, resistant to the action of rimantadine and amantadine. The compounds of the invention inhibit the reproduction of pathogenic influenza virus strains A / IIV-Orenburg / 83/2012 (H1N1) pdm09 and A / H5N1, with a number of compounds having a less toxic effect on the monolayer of MDCK and Vero-E6 cells than rimantadine. Synthesis and biological properties of compounds that are derivatives of 2-norbornane acetic acid are presented in the article: •2-norbornyl acetycarboxylic acid ethyl ester ((ethyl {[(bicyclo [2.2.1] hept-2-ene) acetyl] amino} acetate);•2-norbornyl acetycarboxy-histidine methyl ester ((methyl-2 - {[(bicyclo [2.2.1] hept-2-yl) acetyl] amino} -3- (1H-imidazol-4-yl) proponoate); •2-norbornylcarboxy-tryptophan methyl ester (methyl-3- (1H-indol-3-yl) -2 - [(3- (bicyclo [2.2.1] hept-2-yl) acetyl) amino]propanoate); •2-norbornylcarboxy-glycyl-histidine methyl ester (methyl-3- (1H-imidazol-4-yl) -2- ({[(3- (bicyclo [2.2.1] hept-2-yl) acetyl)amino] acetyl} amino) propanoate); •2-norbornylcarboxy-glycyl-tryptophan methyl ester (methyl-3- (1H-indol-3-yl) -2- ({[(3- (bicyclo [2.2.1] hept-2-yl) acetyl)amino] acetyl} amino) propanoate). These compounds can be used to create new drugs against the influenza A virus, using either as an individual drug or as an ac-tive ingredient in the formulation.

Keywords: 
influenza virus A/H5N1
amino acid derivatives
peptides
2-norbornaneacetic acid
antiviral activity

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