|By: Dr. Erica Ollmann Saphire, PhD|
|The Scripps Research Institute|
|6 Oct 2015|
Efforts to simulate matches between candidate compounds and one key Ebola virus protein are largely complete. Simulations of matches against another, newly discovered target protein are beginning now. Even as simulation work continues, the team is beginning to analyze these results and home in on compounds that could form the basis for effective new drugs against Ebola and other related diseases. Thanks to your help, and a new grant, the work is proceeding well.
Thanks to the efforts of thousands of World Community Grid members, my team has continued to make progress on Outsmart Ebola Together, a project whose goal is to find new drugs for curing Ebola and related life-threatening viral hemorrhagic fevers.
Outsmart Ebola Together began with a study of potential drug attacks against the receptor-binding site of the Ebola surface glycoprotein (GP). We then announced the start of work on a second drug target: the nucleoprotein (NP) of Lassa Fever virus. Specifically, we are looking for drugs that attack the newly discovered "exonuclease site" of Lassa NP. This exonuclease site helps conceal the virus's presence from the infected human cell by destroying the virus's own excess production of double-stranded RNA.
We have since prepared research tasks for testing the Lassa NP exonuclease site against millions of potential drugs. These tasks are now ready for use, and will be sent out to World Community Grid volunteers over the coming months.
Our lab has also been investigating the Ebola NP and VP35 proteins. NP and VP35 must engage in a series of specific interactions with each other as Ebola virus replicates. These newly discovered interactions could potentially be disrupted by new drugs, making NP and VP35 possible future targets for investigation by Outsmart Ebola Together.
At this stage in the project, we’ve gathered enough data that we need to begin focusing on analysis procedures for the data already returned by World Community Grid volunteers. We must analyze the data for both the Ebola GP receptor-binding site and the Lassa NP exonuclease site; and our analysis procedures must be sufficient to filter out false positives from the large quantity of results returned.
For each viral protein site that we test against potential drugs, we assure the validity of our analysis as follows: We select a substantially analogous site (generally from a different virus) for which there exists experimental data about potential drugs that bind or do not bind to the site. We then tune our analysis protocols so that, when applied to this site, our analysis results closely match the known experimental results. Only when this is done do we feel that we can confidently apply the same analysis protocols to the site of current interest.
In particular, this summer we looked closely at analysis optimization for the Lassa NP exonuclease site. As the analogous well-studied site, we chose the "ribonuclease H domain" of HIV reverse transcriptase, which has strong similarities to the Lassa NP exonuclease site in its protein structure and use of catalytic metal ions. The optimization of our analysis protocols against experimental data for the HIV ribonuclease H domain is now complete, and we are looking forward to the arrival of the Lassa NP exonuclease data as it is processed by World Community Grid volunteers. Candidate drugs that pass the analysis stage will go on to a next round of experiments, conducted in the lab rather than by computer simulation.
We are also happy to announce that a $50,000 grant to support this work has been provided by the Robert Wood Johnson Foundation President’s Grant Fund of the Princeton Area Community Foundation. With this grant and the vast computing resources of World Community Grid, our way to the successful completion of the project is clear.
As always, we close with a thank-you to the volunteers who have run this work for us. As you can see, we’ve already made significant progress but there is much work still to do. Make sure you’re signed up to contribute to this project, and spread the word about our lifesaving work!