| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T86674 | ||||
| Target Name | Hemagglutinin | ||||
| Target Type | Successful |
||||
| Action against Disease Model | Arbidol | The antiviral drug arbidol (ARB), which is licensed in Russia for use against influenza, is known to inhibit early membrane fusion events in influenza A and B virus replication.To investigate in more detail the target and mechanism of ARB action we generated and studied the characteristics of ARB-resistant influenza virus mutants. Observations of the ARB susceptibility of reassortants between A/Singapore/1/57(H2N2) and A/chicken/Germany/27(H7N7, "Weybridge" strain) and of mutants of the latter virus identified the virus haemagglutinin (HA) as the major determinant of ARB sensitivity. ARB-resistant mutants, selected from the most sensitive reassortant, possessed single amino acid substitutions in the HA2 subunit which caused an increase in the pH of fusion and the associated conformational change in HA. ARB was shown to stabilize the HA by causing a 0.2 pH unit reduction in the pH of the transition to the low pH form, which was specifically abrogated by the resistance mutations. Some of the resistance mutations, which reduce acid stability and would disrupt ARB-HA interactions, are located in the vicinity of a potential ARB binding site identified using the docking programme Gold. Together, the results of these investigations indicate that ARB falls within a class of inhibitor which interacts with HA to stabilize it against the low pH transition to its fusogenic state and consequently inhibit HA-mediated membrane fusion during influenza virus infection. | [552890] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | In this study we investigate the mechanism of protection after intramuscular vaccination of C57Bl/6 mice with a DNA vaccine encoding HA of influenza A/PR/8/34. After a single injection, only a small percentage of mice survive the lethal challenge with homologous virus. The amount of protection can be doubled by applying a booster injection. Furthermore, by coinjection of plasmids encoding cytokines GM-CSF and IL-12, respectively, nearly all of the mice are protected. Mice with specific defects in the cellular immune response [perforin knockout (P-/-) mice] and in the h uMoral immune response [IgD/IgM knockout (m uMT) mice], respectively, have been immunized with hemagglutinin(HA) DNA with or without cytokine DNA. Protection could only be induced in P-/- mice, whereasm uMT mice succ uMbed to the infection. Moreover, when m uMT mice were infected with only 0.75 x50% lethal dose they died all the same, whereby mice that had been depleted of CD8+ T cells before infection showed an even greater progression of illness. Altogether these results demonstrate that antibodies mediate protection after immunization with plasmid coding for HA of influenza A virus, and that booster immunizations and coinjection of plasmids encoding GM-CSF or IL-12 can improve this protection. | [552890] | |||
| References | |||||
| Ref 552890 | Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol. Antiviral Res. 2009 Feb;81(2):132-40. doi: 10.1016/j.antiviral.2008.10.009. Epub 2008 Nov 24. | ||||
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