[The influenza viruses and their surface proteins impact on the metabolism of human blood vessel endothelium cells].

The modern influenza virus subtypes H3N2, H5N1, and H1N1 reduced the metabolism of the endothelial cells within the range from 20% to 60% (compared with control). The degree of the activity of the dehydrogenase reduction depended on the dose of virus and time of virus reproduction. HA and NA also actively reduced the metabolism of the cells ranging from 5% to 60%, depending on the concentration of the proteins and time of their impact on cells. Neuraminidase was more active than hemagglutinin in the MTT test (at concentration 50 microg protein/ml).

[A new antiviral drug Triazavirin: results of phase II clinical trial].

The results of the clinical trial testing the efficacy of a new anti-influenza drug Triazavirin are presented in this work. The data of the trial were gathered during the 2010 influenza season. The treatment with oral Triazavirin significantly reduced the duration of the main clinical symptoms of influenza (intoxication, fever, respiratory symptoms), decreased the incidence of the influenza-related complications and the use of symptomatic drugs. The re-isolation rate of the influenza A and B viruses was significantly lower in the patients who were using Triazavirin. The analysis of the clinical data showed that the optimal prescribed dosage was 250 mg 3 times a day.

[Development of novel drugs against influenza virus based on synthetic and natural compounds].

Recent progress of the laboratory in the area of the search and development of novel remedies for prophylaxis and treatment of influenza is reviewed in this work. The data of the study of the anti-viral activity of compounds from the chemical groups of azolo-adamantanes, triterpenes, derivatives of benzimidazole, usnic acid, and other heterocyclic substances are presented. The protective properties of the plant antioxidants at lethal influenza infection of animals are discussed. High virus-inhibiting activity of natural polysaccharides and their complexes with silver ions is shown against influenza virus. The data presented allow listed groups of compounds to be suggested as promising candidates for further development of anti-influenza drugs.

[Structure and antiviral activity of adamantane-containing polymer preparation]. / Struktura i antivirusnaia aktivnost' adamantansoderzhashchikh polimernykh preparatov.

New water-soluble antiviral chemical agents, containing 10 to 30% of adamantane derivatives (amino-, aminopropyl-adamantane-, aminomethyl- and rimantadine), which were conjugated with polycarboxylic matrixes of the divinyl ether and maleic anhydride copolymers (DIVEMA), were developed. The polymeric drugs exhibited a low cytotoxicity (4 to 10 times less than rimantadine) and a wide spectrum of antiviral activity against influenza viruses, including both the remantadine-resistant strains of A/PR/8/34 (H1N1) and the B/Saint-Petersburg strain/71/77 as well as against herpes viruses of type 1, parainfluenza viruses of types 1 and 3 and RS-virus. A reduction of the viral infection titer in their reproduction in sensitive cells' cultures was more than 2.0 Ig ID50. Complete inhibition of viral-specific syntheses, registered by immune-enzyme assay (IEA) and by hemagglutination test was observed at low infection doses ranging from 1 to 100 ID50. The efficiency of the antiviral effect depends on a drug's molecular weight and a structure of chemical bonds between the adamantane nucleus and the polymeric matrix.

[Effect of fullerene C60-polyvinilpyrrolidone complexes on influenza virus reproduction]. / Vliianie kompleksov fullerena C60 s polivinilpirrolidonom na reproduktsiiu virusov grippa.

The capacity of water-soluble complexes of fullerene C60-polyvinylpyrrolidone to inhibit the replication of influenza viruses was studied. In contrast to remantadine, these complexes inhibit the replication of both A and B viruses (including the remantadine-resistant strains). The complexes inhibit influenza virus replication at all stages of replication cycle.

[The origin of resistance to chemicals of naturally occurring isolates of influenza A virus]. / Proiskhozhdenie rezistentnosti k khimiopreparatam u prirodnykh izoliatov virusa grippa A.

The mechanisms responsible for the formation of resistance of influenza A virus isolates during the natural circulation of the influenza viruses in the environment were studied. The influenza viruses H1N1 and H3N2 resistant to remantadine, adapromine, and deitiforine have been isolated in the USSR and Mongolia since 1982. The majority of natural resistant isolates appeared to be atypical both in antigenic properties and genomic structure as compared to the isolates prevalent in the common epidemic process. The nucleotide sequences of the M2 gene of some resistant strains and virus A/PR8/34 used in our country as an attenuation donor for preparation of killed recombinant vaccines. The electrophoretic mobility of genomic RNA of two resistant isolates is similar to that of the vaccine strain X-54 based on the virus A/PR/8/34. In this connection, the appearance of resistant strains in the environment may be due not only to spontaneous mutagenesis or selective drug actions, but also to the involvement into the circulation of vaccinal strains.

[Secondary structure of the M2 protein of influenza type A virus and its role in forming resistance to rimantadine and deitiforin]. / Vtorichnaia struktura belka M2 virusa grippa tipa A i ego rol' v formirovanii rezistentnosti k remantadinu i deitiforinu.

Studies of the molecular aspects of resistance of influenza virus A to drugs (rimantadine, deytiforine, amantadine) allow a purposeful design of new compounds with a broad spectrum of antiviral activity and evoking no resistance. In this work the nucleotide sequence of rimantadine- and deytiforine-resistant influenza A strain Leningrad/156/83 (H3N2) was compared with that of A/Victoria/35/72. The influence of aminoacid substitutions in the M2 protein on its secondary structure in the membrane and its role in resistance development was shown.

[The molecular mechanism of the action of antiviral preparations in the adamantane series]. / Molekuliarnyi mekhanizm deistviia antivirusnykh preparatov adamantanovogo riada.

Regions of possible interaction between remantadine and transmembrane M2 protein are revealed by analysis of amino acid substitutions in remantadine- and deutiforin-resistant influenza viruses. The major region includes 5-6 amino acid residues at position 25-31, partially involving the premembrane region and the first position of a hydrophobic membrane-associated domain. The proposed model action of remantadine and its derivatives suggests that remantadine is included into the cell membrane lipid bimolecular layer by its adamantane share and its positively charged NH2-group is exposed to the cell surface. This allows remantadine and its analog to be regarded as molecular "hindrances" for viral particle decapsidation and budding.

[Primary structure of the hemagglutinin gene in strains of the influenza virus A/Leningrad/624/86 and A/Leningrad/621/86 serologic subtype H1N1]. / Pervichnaia struktura gena gemaggliutinina shtammov virusa grippa A/Leningrad/624/86 i A/Leningrad/621/86 seropodtipa H1N1.

A molecular analysis was made of genomes of influenza A (H1N1) virus strains, the causative agents of an epidemic in Leningrad, 1986. The primary structure of hemagglutinin gene of two of these strains, A/Leningrad/624/86 and A/Leningrad/621/86, was established, as well as partial primary structure of PB1 gene of certain current strains of the A (H1N1) subtype. A hypothesis of a "shift" of PB1 gene in 1950-1957 is suggested.

[The isolation and study of the properties of current influenza A viruses (H1N1) with a natural resistance to remantadine]. / Vydelenie i izuchenie svoistv sovremennykh virusov grippa A (H1N1) s prirodnoi rezistentnost'iu k remantadinu.

Studies of influenza A viruses (H1N1) isolated in 1985-1988 revealed 4 strains with natural resistance to chemical drugs (remantadine, adapromine, deitiforin). Three of them were isolated in Mongolia (A/Mongolia/230/85, A/Mongolia/231/85, and A/Mongolia/128/86) and one in the USSR (A/Moscow/771/88). These strains differed from other isolates by the following features: (i) antigenic remoteness from reference A/Chile/1/83 and A/Taiwan/1/86; (ii) similarity in antigenic specificity with A/Khabarovsk/74/77; (iii) resistance to chemical drugs; (iv) high electrophoretic mobility of genes M and NS in PAG. The possible origin of these strains is discussed.

[The change in functional activity and primary structure of the M2 protein in variants of the influenza virus resistant to remantadine and deitiforin: common and individual differences from the original strain]. / Izmenenie funktsional'noi aktivnosti i pervichnoi struktury belka M2 u rezistentnykh k remantadinu i deitiforinu variantov virusa grippa: obschie i individual'nye otlichiia ot iskhodnogo shtamma.

The two variants of influenza A/Victoria/35/72 (H3N2) virus resistant simultaneously to remantadine, deitiforin, adapromine and amantadine were obtained while passaging the virus in presence of remantadine or deitiforin. Both variants differed from the parental strain in optimal pH for hemolysis, transcriptase activity and in amino acid sequence of M2 protein. Maximal hemolytic activity of the parental strain is registered at pH 5.2, for the variants cultured in the presence of remantadine or deitiforin at pH 5.5 and 5.8, respectively. In contrast to NH4OH, remantadine and deitiforin do not exert inhibition of virus-induced hemolysis. Transcriptase activity of resistant variants is about 50% higher as compared with parental strain (enzyme source--whole virus particles or RNP). The M2 protein of the remantadine variant has 2 amino acid substitutions: 31 (Ser----Asn) and 59 (Met----Leu); the deitiforin variant has 3 substitutions: 14 (Met----Leu), 30 (Ala----Val) and 59 (Met----Leu). The phenotypic resistance of the virus seems to be determined by the mutations in the hydrophobic protein region (30,31); the other substitutions (14,59) may modify conformational structure and functional activity of the viral proteins.