233 0007-4888/12/1532-0233 © 2012 Springer Science+Business Media, Inc. New Adamantane Derivatives Can Overcome Resistance of Influenza A(H1N1)pdm2009 and A(H3N2) Viruses to Remantadine V. A. Shibnev, T. M. Garaev, M. P. Finogenova, E. S. Shevchenko, and E. I. Burtseva Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 153, No. 2, pp. 200-202, February, 2012 Original article submitted November 28, 2010 New adamantane derivatives with amino acid residues and other bifunctional compounds were synthesized and their antiviral activity towards influenza A(H1N1)pdm and A(H3N2) viruses was studied. Some of these adamantane derivatives completely suppressed replication of remantadine-resistant influenza A virus strains. Key Words: adamantane derivatives; amino acids; remantadine; influenza A; resistance D. I. Ivanovsky Institute of Virology, Ministry of Health and Social Development of the Russian Federation, Moscow, Russia. Address for correspondence: gtim@fmradio.ru. T. M. Garaev The known methods of influenza treatment and pre- vention include vaccination and drug therapy aimed at infection suppression. The drugs are effective for disease treatment and for its prevention in healthy individuals in contact with sick individuals. Among modern anti-influenza drugs, remantadine and amantadine are most available. Both are adaman- tane compounds suppressing the function of influenza A protein M2. This protein is formed by 4 subunits located in the protein membrane of the virus. The main function of M2 protein is selective transport of protons into the viral particle [7]. Normal functioning of the proton- conducting channel is the key event in the virus rep- lication cycle. Protons transported from the host cell cytoplasm oxidize the medium inside the virion, thus triggering M1 protein deproteinization; after that, ge- netic material of influenza virus enters the cell nucleus for repeated copying of viral RNA. Blockade of M2 channel permeability for hydrogen ions prevents nor- mal reproduction of influenza virus [4]. Studies by spectral methods showed that ada- mantane drugs are fixed in M2 channel via hydrogen bond between the carbocycle amino group and serine residue hydroxyl group in position 31 of the protein transmembrane domain [5]. Wide use of adamantane drugs for influenza treat- ment and prevention led to mutations in influenza vi- rus genome, including position 31 of M2 protein trans- membrane domain with substitution of serine residue for asparagine (Ser31Asn) [9]. This point restructuring of the virus ion channel made impossible fixation of amino-adamantanes in M2 channel. At present, 90% of the known remantadine-resistant influenza viruses carry this substitution that serves as a marker of re- mantadine-resistant strain [6]. Activity of adamantane drugs can be restored via introduction into the adamantane molecule of additional functional groups capable of binding to virus M2 chan- nel proteins. These groups can be donated by amino acid and peptide residues. Being natural elements for the organism, they can form all types of intermolecular bonds, except covalent bonds, and can modulate hydro- phobic/hydrophilic interactions of molecules. MATERIALS AND METHODS Adamantane amino acid derivatives were obtained via the formation of amide bond in the reaction between amino acid carboxyl group and adamantane carbocycle Bulletin of Experimental Biology and Medicine, Vol. 153, No. 2, June, 2012 VIROLOGY