The world has witnessed an unprecedented outbreak of the Ebola virus in West Africa, and Americans have felt the fear brought on by documented cases of the virus within the United States. Health care workers and researchers have made significant efforts to contain and quell the effects of the virus, which has a 70 percent death rate in some areas, but no approved treatment for Ebola yet exists. The search for effective treatments has lagged because of limited supplies of antibody-based therapies, a lack of clinical trials, and the sheer amount of time needed to develop and deploy treatments such as vaccines. Time- and money-saving efforts become critical in such public health crises, and drug repurposing is a viable option that has great potential.
A team of researchers from NCATS and the Icahn School of Medicine at Mount Sinai decided to approach the problem in precisely that way: by screening existing drugs. The study, published in Emerging Microbes and Infections, describes the team’s collaborative efforts to develop a miniaturized assay for high-throughput screening (HTS) to screen for compounds that block the ability of Ebola virus-like particles (VLPs) to enter and infect cells. Because the team is working at biosafety level 2 (BSL-2), the VLPs being studied contain two proteins (glycoprotein and a matrix protein) that enable the virus to enter cells, but these VLPs lack the genes that make the intact virus so deadly.
“While others are using low-throughput screening, we optimized the assay into an HTS format,” said lead author and NCATS researcher Wei Zheng, Ph.D. “Developing a new drug can take 10 to 12 years, but our approach — rapidly testing all currently approved drugs for anti-Ebola activity — offers a faster route to potential discovery of Ebola treatments.”
Drawing from the NCATS Pharmaceutical Collection, a library of 2,816 approved and investigational medicines, the research team identified 53 drugs with Ebola VLP entry-blocking activity. The team identified several distinct classes of compounds, including those previously found to be microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, ion channel/pump antagonists, antibiotics and anticancer drugs. Although further testing must occur before any of these drugs could be used to treat Ebola, the findings provide a jump-start to the development of such treatments.
The research team has already shared its screening results, both positive and negative, with networks for Ebola drug development within NCATS; the National Institute of Allergy and Infectious Diseases, which also is part of the NIH; and the Bill & Melinda Gates Foundation. The results also will be freely available to the public through the National Library of Medicine’s PubChem database. Next steps will require a BSL-4 laboratory, where researchers could continue further evaluation of the drugs’ activities using intact virus infection assays and animal model studies.
“NCATS is all about getting more treatments to more patients more quickly, and this is never more urgent than in a case of a public health emergency like Ebola,” said Christopher P. Austin, M.D., NCATS director. “This remarkable team of scientists combined NCATS’ expertise in drug screening and development with Mount Sinai’s expertise in Ebola virology to rapidly identify candidate treatments for Ebola infection.”
Posted December 2014