Scientists from the University of Copenhagen and Phillips Universität Marburg report that they were able to prevent the Ebola virus from copying itself by inhibiting a specific enzyme. “And that may potentially prevent an Ebola infection from spreading,” says Jakob Nilsson, Ph.D., from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen. The study (“The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30”) is published in Molecular Cell.
“Transcription of the Ebola virus genome depends on the viral transcription factor VP30 in its unphosphorylated form, but the underlying molecular mechanism of VP30 dephosphorylation is unknown. Here we show that the Ebola virus nucleoprotein (NP) recruits the host PP2A-B56 protein phosphatase through a B56-binding LxxIxE motif and that this motif is essential for VP30 dephosphorylation and viral transcription. The LxxIxE motif and the binding site of VP30 in NP are in close proximity, and both binding sites are required for the dephosphorylation of VP30,” write the investigators.
“We generate a specific inhibitor of PP2A-B56 and show that it suppresses Ebola virus transcription and infection. This work dissects the molecular mechanism of VP30 dephosphorylation by PP2A-B56, and it pinpoints this phosphatase as a potential target for therapeutic intervention.”
The team found what they call a new “host factor” in the human body’s own cells for the virus, i.e., the enzyme PP2A-B56, which the virus uses to start producing its own proteins. So if the researchers switch off PP2A-B56, the virus' ability to copy itself and produce more infection is never switched on.
“When we inhibit the PP2A-B56 enzyme, we remove the first link in a long process, which ends with Ebola spreading. And we can tell that it works. The Ebola infection in cell cultures where we have inhibited the PP2A-B56 enzyme is 10 times smaller after 24 hours compared to infections where we have not inhibited this enzyme',” says Dr. Nilsson, adding that the researchers plan to test their approach on animals and, in the long term, develop a drug that inhibits the relevant enzyme.
The potential of the new discovery may turn out to work on other viruses too, because the structure of Ebola virus is very similar to the other so-called filoviruses, and Marburg virus, he continues, noting that whether the same mechanisms apply to them still needs to be uncovered.