Treating Ebola Virus Disease: Scientists Find A Compound That Can Prevent Its Spread
Scientists have found Ebola’s Achilles’ heel: a new kind of chemical compound that can block the protein Ebola uses to break out of cells and infect new cells. The compounds, revealed in a paper in Bioorganic & Medicinal Chemistry Letters, could potentially be used to treat the disease after infection.
The outbreak of Ebola virus disease (EVD) in West Africa between 2013 and 2016 claimed more than 11,000 lives. The global public health threat has led to a resurgence in efforts to tackle the virus with scientific discovery and innovation. Many scientists are now developing vaccines, but they need to be given prophylactically and could only protect against Ebola, leaving people at risk of other hemorrhagic viruses.
Viruses replicate by hijacking the machinery in the cells of their host – in the case of Ebola, human cells – and making the cells build more viruses. Once production is complete, particular virus proteins promote the release of new viruses, which can go on to infect more cells.
When microbiologist Dr. Ronald Harty and his team at the University of Pennsylvania School of Veterinary Medicine in the US came
across a compound that looked like it could interfere with the mechanism viruses use to burst out of cells, they started a project that would take them from looking at structural diagrams on the computer to seeing chemicals tested on live viruses and potentially uncovering a weapon against Ebola virus.Dr. Harty and his team had done a computer-based (in silico) search on some proteins he thought were involved in the process of Ebola virus bursting out of host cells, called egress. Out of millions of chemical compounds they put together a shortlist that looked as if they might bind to and interfere with the protein. He bought and tested some of the compounds and found that one was active – that was the team’s early lead.
The next step was to carry out work to refine the compound. He then worked with Dr. Jay Wrobel of Fox Chase Chemical Diversity Center in the US to evaluate about 20 different commercial chemicals and this led to more potent compounds than the original hit compound. The team prepared and evaluated novel molecules that were even more potent than the original. Their efforts led to a new class of small molecule compounds that target filovirus egress. Dr. Wobel said:
“This was an exciting, interesting and challenging project for me. Exciting because we had the opportunity to find a potential therapeutic agent in a disease area that had caused a lot of human suffering, and where currently no medications exit. Interesting and challenging in that using my intellectual abilities as a medicinal chemist, I find great pleasure in improving the potency and drug properties of chemical matter to find drug candidates.”
The next stage was to look at whether the chemicals worked on viruses. Dr. Harty’s lab can mimic the Ebola and Marburg viruses without the risk of infection, avoiding the need for biocontainment facilities. The research showed that the modified compounds were more than 30 times more potent than the original chemicals at inhibiting virus egress. They also showed that they are stable in human cells – they are not degraded by the cell’s metabolic machinery – and are not toxic to human cells, something Dr. Harty says is significant:
“Positive results showing potent viral inhibition without toxicity to normal healthy cells may lead to a paradigm shift in the search for better antiviral drugs. Importantly, as these virus-host interactions represent a common mechanism used by a range of RNA viruses, we predict that this interaction represents an Achilles’ heel in the life cycle of RNA virus pathogens.”
The research is still in the early stages. The team is now trying to get additional grants and working on even more potent chemicals with better drug-like properties so they can be tested in animal models. The next step will be for the chemicals to be tested on live viruses, then on animal models and eventually they hope to start human trials.
