Screening of existing drugs finds 53 that may prevent Ebola virus infection

6 January 2015

A study led by researchers at the Icahn School of Medicine at Mount Sinai and the US National Institutes of Health (NIH) has found 53 drugs approved for other uses that may keep the Ebola virus from entering human cells, a key step in the process of infection.

The study was published in the journal Emerging Microbes and Infections.

Among the better known drug types shown to hinder infection by an Ebola virus model are several cancer drugs, antihistamines and antibiotics. Among the most effective at keeping the virus out of human cells were microtubule inhibitors used to treat cancer.

“In light of the historic and devastating outbreak of Ebola virus disease, there is an urgent need to rapidly develop useful treatments against Ebola infection, and our study results argue that repurposing existing drugs may be among the fastest ways to achieve this,” said lead author Professor Adolfo García-Sastre of the Icahn School of Medicine at Mount Sinai in the US.

“Many of the compounds identified in this study promise to become lead compounds in near-future drug development efforts studies targeting this virus,” said Prof García-Sastre.

There is no approved treatment for Ebola virus infection, and the estimated mortality rate of the current Ebola outbreak is nearly 70% in many areas. Antibody-based therapy (eg ZMapp) has proven effective in animal studies, and has been used for the treatment of a few patients, but has not been confirmed in clinical trials. It is also expensive to make and in short supply as it requires growing large quantities of genetically altered tobacco plants. Ebola vaccine trials are getting underway as well, but vaccines will not be available for some time.

“NCATS is all about getting more treatments to more patients more quickly, and this is never more urgent than in the case of a public health emergency like Ebola,” said Christopher P. Austin, MD, Director of the National Center for Advancing Translational Sciences (NCATS), part of the NIH, which also led the study. “This remarkable team of scientists combined NCATS’ expertise in drug screening and development with Mt. Sinai’s expertise in Ebola virology to rapidly identified candidate treatments for Ebola infection.”

The research team used high-speed drug screening technology to test sample libraries of 2,816 chemical compounds already approved by the US FDA for other uses. Their test, or assay, was designed to identify compounds that blocked the ability of the Ebola virus to enter and infect human cells by at least 50%.

The team created a virus-like particle comprised of the Ebola proteins (glycoproteins and matrix proteins) that enable the virus to enter cells, but without many of the genes and proteins that make the virus deadly.

They then inserted a fluorescent protein in this virus-like shell so it could be optically tracked using high-speed screening techniques. This showed which drugs blocked the entry of Ebola-like viral particles into human cells.

While fully intact Ebola virus is a biosafety level (BSL) 4 pathogen and dangerous to work with, but the synthetic Ebola virus-like particle is much safer to work with and can be studied in a lower security BSL-2 facility.

The team’s screen yielded 53 drugs that block Ebola virus-like particles from entering human cells. Along with the drug types mentioned above, other categories that blocked viral entry included estrogen receptor modulators used against cancer and serotonin reuptake inhibitors used to treat depression. Some of the compounds had been shown by previous studies to counter Ebola lifecycle steps.

Next steps include testing of the re-purposed drug candidates in animal studies to see if useful doses against the virus come with toxic side effects. If any of prove to be safe and effective, the “government may opt to deploy them in the outbreak areas,” said Dr. García-Sastre.