FOR over five years, a team of U.S. and German researchers led by Yasuteru Sakurai and R.A. Davey of the Texas Biomedical Research Institute has been working on finding therapy targets for the Ebola virus disease. Their present work, published in the latest issue of Science, focussed on stopping the virus before it had a chance to enter or interact with cellular factors. The Ebola virus begins its entry into a cell by first binding to several types of cell surface proteins. Once inside, it is contained in structures called endosomes. To successfully complete the infection, the virus particles make their way through the endosomal membrane and spread throughout the rest of the cell.
Previous studies had shown that during this endosomal process, calcium signalling, which allows cells to transmit electrical charges to one another, controls many of the processes in the cell and was important for Ebola virus infection. Sakurai and his team found that the virus used two calcium pore channels (TPCs) to accomplish this. TPCs are unusual calcium channels that control the way endosomes move through cells and the environment of the cells. This critical role of TPCs has not been identified previously for any other virus.
The researchers also found that these TPCs could be blocked therapeutically with several drugs or with small interfering RNAs. They found that existing drugs used to treat high blood pressure had the ability to turn this key calcium sensor on and off. The team tested several small molecules to see which was most effective at turning the sensors off. Tetrandrine, found in the extract from an Asian herb, was determined to be the most potent blocker of TPCs in mice, allowing half of them to survive a lethal dose of the virus. However, in a related article in the same issue of Science, it was pointed out that tetrandrine was not approved for human use in most countries and that the dose given to mice might be toxic when its equivalent was used in humans.