Promising New Antiviral Compounds Could Treat Ebola Virus Infection
A new kind of chemical compound can block the protein Ebola virus uses to break out of cells and infect new cells, according to a new study by researchers from the University of Pennsylvania and Fox Chase Chemical Diversity Center, Inc.
Scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected cell (yellow-green). Image credit: NIAID.
Viruses replicate by hijacking the machinery in the cells of their host – in the case of Ebola, human cells – and co-opting the cells to help produce more viruses.
Once production is complete, particular virus proteins promote release of viruses from the cell surface, which can go on to infect more cells.
The new compounds, revealed in a paper in the journal Bioorganic & Medicinal Chemistry Letters , target an interaction between the virus and the host cell, inhibiting new Ebola viruses from escaping cells once they have been assembled.
The results show that the compounds block this interaction without being toxic to human cells.
“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,” said study co-author Dr. Ronald Harty, from the University of Pennsylvania School of Veterinary Medicine.
“Importantly, as these virus-host interactions represent a common mechanism used by a range of RNA viruses, we predict that this virus-host interaction may represent an Achilles’ heel in the life cycle of RNA viruses.”
The 2014–2015 outbreak of Ebola in western Africa resulted in over 28,000 infected individuals and claimed more than 11,000 lives.
This unprecedented epidemic has spurred a call to action on new, cost effective therapies that combat this deadly pathogen.
Among the efforts are several vaccines and antiviral candidates. However the current vaccines in clinical trials are not a complete defense.
In response, Dr. Harty and his colleagues wanted to target the Ebola virus’ mechanism for breaking out of cells (egress), which is similar in many different RNA viruses, including Marburg and Lassa fever virus.
The original virus-host interaction they modeled was between Ebola VP40 protein and host protein NEDD4.
The scientists had screened 4.8 million compounds in silico to find one that was shown to prevent VP40-NEDD4 interactions, therefore blocking virus egress.
They then evaluated about 20 different commercial chemicals and this led to more potent compounds than the original hit compound.
They 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 virus egress.
The modified compounds were more than 30 times more potent than the original chemicals at inhibiting virus egress. They also showed that they do not interfere with human cell metabolism for breaking down chemicals, and are not toxic to human cells.
The primary use of the new antiviral compounds is expected to be in treating people already infected, but it could also potentially be used prophylactically, for example in soldiers and healthcare workers.
“We postulate that emergency administration of such an antiviral therapeutics during an outbreak would inhibit virus dissemination and spread in infected individuals, thus slowing disease progression and allowing the immune system more time to mount a robust response to effectively combat and clear the infection,” said lead author Dr. Jay Wrobel, from Fox Chase Chemical Diversity Center, Inc.