From WCG: Ebola outbreak

World Community Grid (WCG)

The World Health Organization just announced three recent deaths from Ebola in the Democratic Republic of Congo, which may grown into a new outbreak of the disease. Please support the Outsmart Ebola Together project and help scientists find better treatments for this deadly virus.

Outsmart Ebola Together

You can help researchers at The Scripps Research Institute find a cure for Ebola by donating your computing power to this project and encouraging others to join.

You can also support the research team by contributing to The Scripps Research Institute’s crowdfunding campaign. The team will use these funds to analyze the enormous volume of data generated by Outsmart Ebola Together and study the most promising drug candidates.

The Ebola virus is a significant global health threat and is a growing humanitarian crisis in Africa, killing thousands of victims in 2014.

http://www.webmd.com/a-to-z-guides/ebola-fever-virus-infection

If not handled properly, an Ebola outbreak can turn into an epidemic, overwhelming regional health services and disrupting trade and the delivery of social services, causing the welfare and economy of a region to deteriorate. The ongoing viral load in the human population increases the likelihood of further mutation. Additionally, the virus’s long incubation period and our highly connected modern world could allow the virus to spread to new geographies and across oceans.

Currently, there are no approved treatments or vaccines for this deadly disease, and the search for an effective antiviral drug to treat the disease is a high priority. While previous outbreaks have ended when the disease disappeared from the human population, the scope of the 2014 outbreak raises the possibility that the virus, rather than disappearing again, could become endemic – permanently persisting in human populations in one or more areas.

Outsmart Ebola Together on World Community Grid aims to help researchers at The Scripps Research Institute develop a treatment for Ebola virus. The computational power donated by World Community Grid volunteers is being used to screen millions of candidate drug molecules to identify ones that can disable the Ebola virus.

See the full article here.

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“World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”
WCG projects run on BOINC software from UC Berkeley.

BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

My BOINC

“Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

Please visit the project pages-

FightAIDS@home Phase II

OpenZika

Help Stop TB

Outsmart Ebola together

Mapping Cancer Markers

Uncovering Genome Mysteries

Say No to Schistosoma

GO Fight Against Malaria

Drug Search for Leishmaniasis

Computing for Clean Water

The Clean Energy Project

Discovering Dengue Drugs – Together

Help Cure Muscular Dystrophy

Help Fight Childhood Cancer

Help Conquer Cancer

Human Proteome Folding

FightAIDS@Home

World Community Grid is a social initiative of IBM Corporation
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IBM – Smarter Planet

From Vanderbilt: “Investigators create ‘Trojan Horse’ to fight Ebola”

Vanderbilt University

Sep. 8, 2016
Bill Snyder
william.snyder@Vanderbilt.Edu
(615) 322-4747

A multi-center research team including scientists from the Vanderbilt Vaccine Center has come up with a clever “Trojan Horse” strategy for thwarting the highly lethal Ebola virus.

Using “bispecific” antibodies — two monoclonal antibodies combined into a single package — they first tricked the virus into revealing a normally hidden binding site required for infection. Then in a mouse model, they blocked the site, fully protecting the animals from Ebola infection.

Their findings, reported in this week’s Science magazine, suggest that this two-step, “deliver-and-block” strategy can provide broad protection against Ebola and other members of its hemorrhagic filovirus family, including the Marburg virus.

We were intrigued to find this remarkable antibody that has the capacity to inhibit both Marburg and Ebola viruses,” said James Crowe Jr., M.D., Ann Scott Carell Professor in the Vanderbilt University School of Medicine and director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center.

“The team’s feat of delivering the antibody into cells using creative engineering tricks so that it can kill Ebola inside cells is very exciting,” Crowe said.

This advance is only the latest in a string of fundamental discoveries made during the past decade by a far-flung group of researchers including Crowe and four other corresponding authors of the paper.

The four are Kartik Chandran, Ph.D., and Jonathan Lai, Ph.D., of Albert Einstein College of Medicine in New York, John Dye, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, and Javad Aman, Ph.D., of Integrated Biotherapeutics in Gaithersburg, Maryland.

Like other viruses, Ebola must “hijack” factors in the cells it infects to make copies of itself. As a first step, the virus enters a vesicle called an endosome inside the cell. There it commandeers two cellular enzymes called proteases to cut a sugar-bearing glycoprotein on its surface in two.

Cleavage of the glycoprotein reveals a previously hidden receptor-binding site that attaches to another cellular factor, a cholesterol transporter protein called Niemann–Pick C1 or NPC1. This step is essential for infection to occur.

Mutations in the NPC1 gene result in an abnormal protein that causes the rare lipid storage disorder Niemann-Pick type C disease. While patients with this disease are often quite ill, their abnormal NPC1 protein also renders them resistant to infection by Ebola and the related Marburg virus.

Last year, Crowe, Vanderbilt graduate student Andrew Flyak and colleagues at The Scripps Research Institute in La Jolla, California, reported that a human survivor of a severe Marburg infection had neutralizing antibodies that recognized and blocked the NPC1 binding site in Marburg virus

These antibodies also could bind to the Ebola virus, but only to the form of the virus inside cells.

Crowe and Flyak followed up that finding by generating a “monoclonal” antibody, called MR72, which specifically recognized and could block the NPC1 binding site. To actually prevent Ebola virus infection, however, they’d have to get the antibody into the endosome inside the cell where the action is taking place.

To do that, the researchers fused MR72 to another antibody, called FVM09, which recognizes and attaches to the Ebola glycoprotein before it is cut in two. The result was an immunological “Trojan horse.” Once the virus brought its antibody cargo into the endosome, MR72 went to work, and blocked infection.

“This Trojan horse bispecific antibody approach may also find utility against other viral pathogens known to use intracellular receptors,” they concluded.

Other contributors to the current study were Erica Ollmann Saphire, Ph.D., at Scripps and Zachary Bornholdt, Ph.D., now at Mapp Pharmaceutical in San Diego. The study was supported in part by National Institutes of Health grants AI109762, AI088027 and AI122403.

See the full article here .

You can Help Stamp Out EBOLA.

This WCG project runs at Scripps Institute

Visit World Community Grid (WCG). Download and install the BOINC software on which it runs. Attach to the Outsmart Ebola Together project. This will allow WCG to use your computer’s free CPU cycles to process computational data for the project.

While you are at WCG and BOINC, check out the other very worthwhile projects running on this software. All project results are “open source”, free for the use of scientists world while to advance health and other issues of mankind.

Please help promote STEM in your local schools.

Stem Education Coalition

From Scripps: “Team Pinpoints Ebola’s Weak Spots”

Scripps Research Institute

8.12.16
Madeline McCurry-Schmidt

Scientists at The Scripps Research Institute (TSRI) now have a high-resolution view of exactly how the experimental therapy ZMapp™ targets Ebola virus.

The new study is also the first to show how an antibody in the ZMapp™ “drug cocktail” targets a second Ebola virus protein, called sGP, whose vulnerable spots had previously been unknown.

“This sGP protein is tremendously important,” said TSRI Professor Erica Ollmann Saphire, who co-led the study with TSRI Associate Professor Andrew Ward. “This is the roadmap we need to target the right molecules in infection.”

“Determining the proper balance in targeting these two Ebola proteins will be key to building improved therapeutics,” added Ward.

The study was published August 8, 2016 in the journal Nature Microbiology.

The team succeeded in showing how experimental therapy ZMapp™ targets the Ebola virus, here pictured targeting the virus’s GP protein. (Image courtesy of Andrew Ward and Jesper Pallesen.)

Zooming in on ZMapp™

Scientists need detailed images of Ebola virus’s molecular structure. Like enemy reconnaissance, structures can show where Ebola is vulnerable and how medical treatments can neutralize it.

TSRI scientists are harnessing an imaging technique called cryo-electron microscopy (in which a sample is pelted with electrons) to create high-resolution, 3-D images of Ebola virus and the antibodies that fight it.

“We’re at the cutting edge of our ability to resolve high-resolution protein complexes,” said TSRI Research Associate C. Daniel Murin, co-first author of the new study with TSRI Research Associate Jesper Pallesen.

In the new study, the researchers used cryo-electron microscopy to see exactly how Ebola virus interacts with the three antibodies in the ZMapp™ experimental therapy produced by Mapp Biopharmaceutical, also a study collaborator.

The researchers had imaged these interactions at a low resolution in a 2014 study, but the new study revealed substantially more details, including the exact angles the antibodies use to approach the molecule on the surface of the virus, termed its surface glycoprotein (GP), and the individual amino acid contact points at which the antibodies bind GP. This information provides new clues to researchers trying to make the antibodies even more effective.

“The three components of ZMapp™, now resolved at high-resolution, can be further engineered in a structure-based manner for improved potency,” said Ward.

Solving an Elusive Structure

Next, the researchers took a closer look at one of the three antibodies that make up ZMapp™, called 13C6. This antibody is unique because it can also target the soluble Ebola protein sGP.

sGP’s role in infection is a mystery. Ebola virus makes the protein profusely, indicating that it is important, but then sGP appears just to float in a person’s blood serum. One theory is that sGP may be essential in the natural host “reservoir.”

“Eighty to ninety percent of what Ebola virus makes in infection is this shed molecule,” said Saphire. “It’s like a smoke screen, and we need to know where it is similar to our target GP and where it is different.”

To add to the mystery, Ebola makes GP and sGP using the same gene. A small difference in the way the gene is read changes how the molecules are shaped and changes their roles.

One obstacle to understanding sGP is that it is too small to be seen with cryo-electron microscopes. To solve this problem, the researchers added “bulk” by pairing sGP with antibodies, including 13C6. This allowed them to kill two birds with one stone—they could see sGP’s structure while also studying how antibodies interact with it.

The new image shows the binding sites, or “epitopes,” the antibody targets. “We can see hot spots on this virus that we can hit,” said Pallesen.

This study is the latest research from the Viral Hemorrhagic Fever Consortium, an international partnership of research institutes led by Saphire. The researchers said collaboration with the consortium was key to this study, allowing scientists to share samples and data, including viral genetic sequences isolated from patients in the most recent Ebola outbreak.

In addition to Saphire, Ward, Murin and Pallesen, authors of the study, Structures of Ebola virus GP and sGP in complex with therapeutic antibodies, were Natalia de Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah Turner and Marnie Fusco of TSRI; Kristian G. Andersen of TSRI and the Scripps Translational Science Institute; Andrew I. Flyak and James E. Crowe of Vanderbilt University and Larry Zeitlin of Mapp Biopharmaceutical.

This study was supported by the National Institutes of Health (NIH, grant R01 AI067927), the NIH’s National Institute of Allergy and Infectious Diseases (grants U19AI109762 and U19AI109711) and the National Science Foundation.

See the full article here .

You can Help Stamp Out EBOLA.

This WCG project rubs at Scripps Institute

You can help researchers at The Scripps Research Institute find a cure for Ebola by donating your computing power to this project and encouraging others to join.

Please help promote STEM in your local schools.

Stem Education Coalition

The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

From Outsmart Ebola Together at WCG: “Summer Plans for Outsmart Ebola Together”

World Community Grid (WCG)

9 Jul 2016
Dr. Erica Ollmann Saphire, PhD
The Scripps Research Institute

Summary
In this brief update, Dr. Erica Saphire talks about the continuing need for research on the Ebola virus, and the search for funding to help analyze the data generated so far by World Community Grid volunteers.

Access mp4 video here .

As of June 2016, the World Health Organization (WHO) reports that there have been more than 28,000 cases of the Ebola virus in Guinea, Liberia and Sierra Leone, with more than 11,000 deaths. While WHO has declared that the most recent outbreak has ended, most researchers and public health experts believe that it is only a matter of time before another Ebola virus outbreak occurs. Sudan virus and Marburg virus, two diseases that are related to the Ebola virus, can also cause severe hemorrhaging and have high potential for outbreaks. Lassa virus also causes similar symptoms and is endemic, causing thousands of cases every year in Western Africa.

For these reasons, our research is crucial to helping contain future disease outbreaks. In order to move more rapidly towards laboratory testing of the most promising compounds screened on World Community Grid, we are looking for funding to hire an additional lab member that would be shared between our lab and the Olson Laboratory here at The Scripps Research Institute. This person would help with data analysis for Outsmart Ebola Together and Fight AIDS@Home and would also help prepare the future targets for Ebola and related diseases for us to explore using World Community Grid.

Funding is always an issue in scientific research, and resources are becoming more scarce for science throughout the world. But Outsmart Ebola Together remains a top priority for my lab, and our work will continue. We are very grateful to the many volunteers who continue to contribute to this project. We look forward to announcing receiving funding for a new position in the future!

See the full article here.

You can help stamp out EBOLA.
Visit World Community Grid (WCG). Download and install the BOINC software on which it runs. Attach to the Outsmart Ebola Together project. This will allow WCG to use your computer’s free CPU cycles to process computational data for the project.

Please help promote STEM in your local schools.

Stem Education Coalition

WCG projects run on BOINC software from UC Berkeley.

BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

“Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

Please visit the project pages-

FightAIDS@home Phase II

OpenZika

Help Stop TB

Outsmart Ebola together

Mapping Cancer Markers

Uncovering Genome Mysteries

Say No to Schistosoma

GO Fight Against Malaria

Drug Search for Leishmaniasis

Computing for Clean Water

The Clean Energy Project

Discovering Dengue Drugs – Together

Help Cure Muscular Dystrophy

Help Fight Childhood Cancer

Help Conquer Cancer

Human Proteome Folding

FightAIDS@Home

World Community Grid is a social initiative of IBM Corporation
IBM Corporation
ibm

IBM – Smarter Planet

From “Outsmart Ebola Together” at WCG

21 Mar 2016
Dr. Erica Ollmann Saphire, PhD
The Scripps Research Institute

Summary
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, 33.4 million of these virtual experiments have been conducted 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.

See the full article here.

Please help promote STEM in your local schools.

Stem Education Coalition

WCG projects run on BOINC software from UC Berkeley.

BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

Please visit the project pages-
Outsmart Ebola together

Mapping Cancer Markers

Uncovering Genome Mysteries

Say No to Schistosoma

GO Fight Against Malaria

Drug Search for Leishmaniasis

Computing for Clean Water

The Clean Energy Project

Discovering Dengue Drugs – Together

Help Cure Muscular Dystrophy

Help Fight Childhood Cancer

Help Conquer Cancer

Human Proteome Folding

FightAIDS@Home

World Community Grid is a social initiative of IBM Corporation
IBM Corporation
ibm

IBM – Smarter Planet

From Nature: “Ebola re-emerges in Sierra Leone”

Nature

15 January 2016
Richard Van Noorden

A treatment facility in the Lunsar Ebola Treatment Centre in Port Loko, Sierra Leone. Pete Muller/National Geographic Creative

When the World Health Organization (WHO) declared on 14 January that the spread of Ebola had been halted in West Africa, it cautioned that cases of the virus might yet re-emerge. That is exactly what has happened in Sierra Leone, where another death from Ebola was announced hours after the WHO’s statement.

Health officials told reporters that a 22-year-old woman had died in Magburaka after falling ill in Baomoi Luma, near the border of Guinea. A test for Ebola was confirmed positive only after her death, which occurred earlier in the week, raising concerns that she may have been in contact with others while contagious.

The case is Sierra Leone’s first since it was declared free of Ebola on 7 November 2015, although the country was still in a 90-day period of enhanced surveillance. The WHO and local partners say that they are investigating its origin and identifying the woman’s contacts.

Flare-ups expected

Although the epidemic phase of Ebola seems to be over, isolated cases were expected. The WHO considers human transmission of the virus to have halted when a country has gone 42 days (twice the virus’s incubation period) with no new cases — but the virus can persist in survivors for months in semen, as well as in tissues such as the eye, the central nervous system, the prostate gland and the placenta. It also remains hidden in animal reservoirs.

Liberia, for example, was pronounced Ebola-free in May 2015, but the virus flared up twice before the WHO could declare the country clear of the virus again on 14 January. “We are now at a critical period in the Ebola epidemic as we move from managing cases and patients to managing the residual risk of new infections,” Bruce Aylward, special representative for the WHO’s Ebola response, noted in the organization’s press-released statement at the time.

There is a particular focus on the potential of sexual transmission of Ebola to cause occasional cases. After a first-known case of sexual transmission of the disease was confirmed in Liberia last October, Armand Sprecher, a public-health specialist with Médecins Sans Frontières (also known as Doctors without Borders) in Brussels, wrote in an editorial: “The challenge with sexual transmission is not that it would be a source of many new Ebola virus disease cases, but that it may be a source of late cases.”

Nature doi:10.1038/nature.2016.19180

See the full article here .

Want to help in the fight against Ebola? You can help from the comfort of your home by contributing unused CPU cycles of your personal computer (Windows, Mac, Linux) to World Community Grid’s (WCG) Outsmart Ebola Together project. Join WCG, attach to the project, let your computer do the data computation.

WCG runs on BOINC software from UC Berkeley.

Please help promote STEM in your local schools.

Stem Education Coalition

Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

From Outsmart Ebola Together at WCG: “Finding new avenues to attack Ebola”

6 Oct 2015
Dr. Erica Ollmann Saphire, PhD, The Scripps Research Institute

Summary
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.

Two Protein Data Bank structures for the ribonuclease H domain of HIV reverse transcriptase. We used structural and experimental data for this domain to optimize our analysis protocols for the Lassa NP exonuclease site.

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!

See the full article here.

Please help promote STEM in your local schools.

Stem Education Coalition

CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!

Please visit the project pages-
Outsmart Ebola together

Mapping Cancer Markers

Uncovering Genome Mysteries

Say No to Schistosoma

GO Fight Against Malaria

Drug Search for Leishmaniasis

Computing for Clean Water

The Clean Energy Project

Discovering Dengue Drugs – Together

Help Cure Muscular Dystrophy

Help Fight Childhood Cancer

Help Conquer Cancer

Human Proteome Folding

FightAIDS@Home

World Community Grid is a social initiative of IBM Corporation
IBM Corporation
ibm

IBM – Smarter Planet

From WCG “A milestone and a roadmap: progress in the fight against Ebola”

5 May 2015
The Outsmart Ebola Together research team

Summary
Thanks to the huge level of support from World Community Grid, the team at the Scripps Research Institute has already received most of the matching data for the first target protein of the Ebola virus. While this data is being analyzed, the search now moves to another related protein with potential to help the fight against hemorrhagic fevers.

Outsmart Ebola Together, a long-term scientific project whose goal is to find new drugs for curing Ebola and related life-threatening viral hemorrhagic fevers, is still in its early stages, but we’ve already reached a major milestone. Our first target was the newly revealed receptor-binding site of the Ebola surface protein, GP. GP is the molecule Ebola virus uses to fuse with a human cell and force its way inside. Armed with a new model of the binding site, and with the vast resources of World Community Grid, we set out to test this site against drugs that could potentially bond with it and prevent Ebola infection. This stage of work is now close to complete: we have received back from World Community Grid most of the data for the planned matchings of the Ebola surface protein against 5.4 million candidate chemical compounds.

We are now analyzing this data. Drugs that simulations predict will bind well with the Ebola surface protein will go on to a next round of experiments, conducted in the lab with actual proteins and actual drug molecules. Our analysis may also yield general insights about how classes of drugs interact with viral proteins.

Moreover, we are excited to announce that we are beginning work on a second target protein, the Lassa virus nucleoprotein.

Like Ebola, Lassa is a “Group V” virus: in other words, both are viruses that have at their core a genome composed of “negative-sense”, single-stranded RNA. Both viruses produce a deadly hemorrhagic fever. While Lassa has received less publicity than Ebola, it is a more consistent killer. There are hundreds of thousands of cases of Lassa Fever every year in Western Africa, with tens of thousands of deaths. It is also the viral hemorrhagic fever most frequently transported out of Africa to the United States and Europe. There are no treatments approved for use in Lassa virus infection. Identification of a potent inhibitor of Lassa virus is imperative for public health.

The Lassa virus’s nucleoprotein (NP) is so named because its first discovered function is to bind with, and so enclose and protect, the virus’s central strand of RNA. However, Lassa NP is a complex beast that has other functions as well. In particular, our lab discovered that the NP (almost paradoxically) is also responsible for digesting double-stranded RNA (dsRNA) created by the virus itself. Having gained entry to a human cell, the Lassa virus must copy its single-stranded RNA in order to produce viral proteins and replicate itself. This requires creating double-stranded RNA. However, the virus must keep this work secret. The presence of double-stranded RNA in the cytoplasm is a clear sign of a viral infection, and human cells are smart enough to detect this, triggering an effective immune response. Hence the importance of the Lassa NP, which rips apart the virus’s own dsRNA byproducts in order to keep its activities secret.

We approach Lassa NP armed with our lab’s crystallographic structures, which clearly identify the shape of the NP and the site where the NP carries out its function of destroying double-stranded RNA. This site is a large cavity in the side of the protein; it is negatively charged, but is also bordered by a positively charged, protruding protein “arm”. These distinctive features are key to the site’s binding with dsRNA, and, we believe, should make it a good candidate for screenings against possible drugs.

Figure: Our lab’s structure for the Lassa NP protein. Portions important to the protein’s function of digesting double-stranded RNA include the “cavity” (glowing, particularly a manganese atom that helps bond RNA) and the adjacent “arm” (yellow).

We will now prepare this target protein for matchings against millions of drugs using the resources of the World Community Grid. As with our previous matchings against the Ebola surface protein, drugs that do well in this “virtual screening” will go on to further tests with actual proteins in the lab. While this work is difficult and carries no guarantees, we hope that it will lead to the discovery of a drug that can prevent the Lassa NP from hiding the virus’s double-stranded RNA. We have already determined that doing this would allow human cells to detect and act against the Lassa virus more promptly and effectively, potentially saving lives.

It’s amazing to us that we’ve been able to receive so many results so quickly, and we want to say thank you to everyone in the World Community Grid family who helped make this possible. There is much work ahead, but it’s immensely encouraging to know that we have the resources available to carry it out.

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