|By: Dr. Erica Ollmann Saphire, PhD|
|The Scripps Research Institute|
|21 Mar 2016|
In this project update, Dr. Erica Ollman Sapphire covers many fronts on the fight against Ebola, from the long-term effects of the disease on survivors, to her team's continued experiments using World Community Grid and their work with other Ebola researchers.
The Long-Term Effects of the Ebola Epidemic
As the bulk of the Ebola virus epidemic winds down, we see long-term effects of the infection in survivors. For some, the virus has entered the central nervous system, causing re-emergence of meningitis-like disease, severe eye pain, loss of vision and other complications. Evidence of the virus has been isolated from the semen of survivors up to nine months after release from treatment centers. This has likely resulted in at least one case of sexually transmitted Ebola virus. Additional cases of Ebola virus have erupted in Sierra Leone and in Liberia after each country was declared free of human-to-human transmission. Appearance of these new cases means that the virus is likely still in the ecological reservoir or is being re-introduced into the environment or to other humans. At the same time, survivors face numerous health challenges, economic challenges, personal losses and social stigmas.
Searching for Effective Treatments
The need for small molecule drugs that can treat Ebola virus infection remains. Small molecules that could cross the blood-brain barrier could be used to treat the life-threatening cases in which the virus expanded in the central nervous system long after release from the clinic. Importantly, such molecules must not only be developed against Ebola virus but against similar viruses that could cause the next outbreak.
The goal of Outsmart Ebola Together is to identify candidate drugs active against Ebola virus, Lassa virus and other related health threats. To accomplish this goal, we are studying the atomic structure of the target, which is the Ebola virus molecule, and the ligands, which are the structures of millions of candidate drug molecules. The target and ligand are evaluated against one another, and a software program computes the tendency of the molecules to associate with each other. Simulating these experiments on computers saves considerable time and cost, because laboratory testing requires purchasing or synthesizing the candidate molecules, a potentially time-consuming and expensive process.
So far, there have been an estimated 200 million virtual dockings for the over 135 million results returned by World Community Grid volunteers, the percentage of tasks completed is increasing, and will probably reach 100% soon. We are currently seeking a computational scientist (and funding to support him or her) to filter this tremendous body of work into the most meaningful compounds we can test in a laboratory.
Recent Publications and Continuing Work
In the meantime, new targets are planned. Recently, we solved the structures of the protein of Marburg virus that builds and releases new viruses from the infected cell, while simultaneously silencing the ability of our cells to detect and fight the infection (Oda, et al. Journal of Virology, Crystal structure of Marburg virus VP40: matrix assembly and immunosuppression). In that effort, we are working with an excellent team of biophysicists at Notre Dame University, led by Dr. Robert Stahelin, to understand how the virus interacts with and hijacks the membranes of our cells. Understanding the structure of the Marburg virus is important because, like the Ebola virus, it can cause fever, severe bleeding, organ failure, and, in many cases, death.
Our structure of the molecule that achieves the same functions for Lassa virus--which can also cause severe bleeding, fever, and death--will be released soon (Hastie, et al. in press).
A collaborative team involving my lab has searched in the blood of a survivor of this Ebola outbreak to find some of the highest potency antibodies yet identified (Bornholdt, et al. 2016 Science, Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak). This group is part of the global consortium that gathers and analyze antibodies against these deadly viruses, and we were recently featured on the show Breakthrough by National Geographic.
We thank all World Community Grid volunteers who have donated computing power to Outsmart Ebola Together, and we are grateful for your continued support as the project progresses.
(This article was updated on April 22 to correct the number of estimated virtual dockings completed by volunteers.)