Oct 30, 2015
In a new study published in the journal Science, tetrandrine – an alkaloid found in Stephania tetrandra (commonly known as stephania root or ‘han fang ji’) and other Japanese and Chinese herbs – inhibited infection of human white blood cells in petri dish experiments and also showed therapeutic efficacy in lab mice.
Ebola is a rare and deadly disease caused by infection with a virus of the familyFiloviridae, genus Ebolavirus.
There are five identified Ebolavirus species, four of which are known to cause disease in humans: Ebola virus, Sudan virus, Taï Forest virus, and Bundibugyo virus. The fifth, Reston virus, has caused disease in nonhuman primates, but not in humans.
Ebola was first discovered in 1976 near the Ebola River in the Democratic Republic of the Congo and currently has no approved therapy or vaccine.
The new study, led by Dr Robert Davey of the Texas Biomedical Research Institute, focused on stopping the Ebola virus before it has a chance to enter or interact with cellular factors, as that is a critical first step to combating infection.
The virus begins its entry into a cell by first binding to several types of cell surface proteins. Then the virus is taken into the cell and follows an endosomal route, or membrane-bound route that transports the virus to various cell compartments.
From previous studies, Dr Davey and his colleagues from Germany and the United States knew that calcium signaling in cells, which allow cells to transmit electrical charges to one another, controls many of the processes in the cell and was important for Ebola virus infection.
“We were not able, however, to pinpoint the mechanisms involved in this process,” Dr Davey said.
“With this research, we discovered that two pore channels (TPCs) are the key calcium sensor involved in Ebola virus infection. These TPCs essentially need to be turned on in order for the virus to function properly.”
Two pore channels are unusual calcium channels found in endosomes that control the way endosomes move through cells and the environment of the cells.
The scientists compared TPCs to traffic cops and air conditioners, helping direct the endosomes and any virus it might be carrying through the cell and making the endosomes and its passengers more comfortable along the way.
They were able to show the critical role of two pore channels in Ebola virus infection, which has not previously been shown in any other virus.
In addition to identifying this critical mechanism to infection, the researchers also showed that drugs targeting this interaction show some efficacy as potential treatments against Ebola virus disease.
They determined that existing drugs currently used to treat high blood pressure have an ability to turn this key calcium sensor on and off. They tested several small molecules to see which was most effective at turning the sensors off thus prohibiting Ebola virus from moving any further through the cell.
The scientists found a compound called tetrandrine protected mice from disease without obvious side effects and was the best candidate for further animal testing, because it was the most potent compound tested, gave little evidence of cytotoxicity and required a smaller dose to be effective and tolerated.
“When we tested in mice, the drugs stopped virus replication and saved most of them from disease,” Dr Davey said.
Essentially, tetrandrine shows an ability to stop the virus before it has a chance interact with cellular factors, thus stopping the virus from continuing its infection process.
“We are very excited about the progress made in this study and the momentum it provides as scientists across the world vigorously search for effective vaccines and treatments against Ebola virus,” Dr Davey said.
“We are cautiously optimistic. The next step in the process is to test both safety and effectiveness of the interaction of the drug with Ebola virus in non-human primates.”
Yasuteru Sakurai et al. 2015. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science, vol. 347, no. 6225, pp. 995-998; doi: 10.1126/science.1258758