Researchers at St. Jude Children’s Research Hospital have discovered a potential drug target which would inhibit an enzyme necessary for the influenza virus replication. The study is published in the journal PLoS Pathogens.
Influenza viruses can often turn into a pandemic and leave researchers very little time to produce an effective vaccine against them. The H1N1 virus, AKA swine flu, scare that recently occurred in 2009 originated in swine, but more recently researchers are concerned over the Avian Flu H5N1 and the potential threat it might pose to humans if it evolves an effective means to do so.
One thing St. Jude researchers found is that these various strains of influenza have a common mechanism for replication and that is an enzyme called polymerase. Polymerase is vital to the process that the flu virus uses to replicate itself and according to a St. Jude press release, “hijack the cell’s machinery to make it produce more virus”. It’s truly amazing how these viruses replicate themselves. They use a subunit of polymerase complex called endonuclease which enables the virus to disguise its messenger RNA as that of the cell it’s trying to take over. This enzyme snips a piece of the cell’s mRNA referred to as the “cap” and puts it on its own virulent strand. The next thing you know, the cell is now a factory for building the virus.
“Inhibitors of the polymerase complex would make excellent drug candidates,” said Stephen White, DPhil., chair of the St. Jude Structural Biology department and the study’s senior author. “It is a good target because these polymerases are essentially the same across many strains, and also because the virus absolutely needs the polymerase to make copies of itself. The polymerase doesn’t have very many similarities to other polymerases in cells, so it should be fairly specific for the flu polymerase.”
The researchers developed a “warhead” to attack endonuclease at its active site. The active site is where the chemical reaction of mRNA stripping takes place. The “warhead” is basically a molecule designed to bind itself to a central pocket in the active site. “By analyzing the structure of the active site with the drugs bound to it, we have identified a number of pockets inside the active site of the protein,” said study first author Rebecca DuBois, Ph.D., a postdoctoral research fellow in the St. Jude Structural Biology department. “We can use these structures to develop drugs that will specifically target certain pockets. Now that we know which pockets are really conserved, we can predict the best way to avoid the development of resistance by viral strains.”
The next step will be to work with a pharmaceutical to produce and perfect compounds that could effectively target the PA protein. Then the step of clinical trials could begin. St. Jude researchers believe that this research could lead to a valuable “first strike” drug to target influenza in hospitalized patients.
To learn more about St. Jude and their ongoing research, visit their website at http://www.stjude.org.