Ebola Archives - Sanford Burnham Prebys
Institute News

Battling infectious diseases with 3D structures

AuthorSusan Gammon, PhD
Date

April 25, 2017

Sanford Burnham Prebys Medical Discovery Institute (SBP) scientists are part of an international team led by Northwestern University Feinberg School of Medicine that has determined the 3D atomic structure of more than 1,000 proteins that are potential drug and vaccine targets to combat some of the world’s most dangerous emerging and re-emerging infectious diseases.

These experimentally determined structures have been deposited into the World-Wide Protein Data Bank, an archive supported by the National Institutes of Health (NIH), and are freely available to the scientific community. The 3D structures help expedite drug and vaccine research and advance the understanding of pathogens and organisms causing infectious disease.

“Almost 50 percent of the structures that we have deposited in the Protein Data Bank are proteins that were requested by scientific investigators from around the world,” said Feinberg’s Wayne Anderson, PhD, director of the project. “The NIH has also requested us to work on proteins for potential drug targets or vaccine candidates for many diseases, such as the Ebola virus, the Zika virus and antibiotic-resistant bacteria. We have determined several key structures from these priority organisms and published the results in high-impact journals such as Nature and Cell.

Teamwork with an international consortium

This milestone effort, funded by two five-year contracts from the National Institute of Allergy and Infectious Diseases (NIAID), totaling a budget of $57.7 million, represents a decade of work by the Center for Structural Genomics of Infectious Diseases (CSGID) at Feinberg, led by Anderson in partnership with these institutions:

  • University of Chicago
  • University of Virginia School of Medicine
  • University of Calgary
  • University of Toronto
  • Washington University School of Medicine in St. Louis
  • UT Southwestern Medical Center
  • J. Craig Venter Institute
  • Sanford Burnham Prebys Medical Discovery Institute
  • University College London

How the 3D structures are made

Before work begins on a targeted protein, a board appointed by the NIH examines each request. Once approved, the protein must be cloned, expressed and crystallized, and then X-ray diffraction data is collected at the Advanced Photon Source at Argonne National Laboratory. This data defines the location of each of the hundreds or even thousands of atoms to generate 3-D models of the structures that can be analyzed with graphics software. Each institution in the Center has an area of expertise it contributes to the project, working in parallel on many requests at once.

The bioinformatics group SBP, led by Adam Godzik, PhD, focuses on steps that have to be taken before the experimental work starts. Every protein suggested by the research community as a target for experimental structure determination is analyzed and an optimal procedure for its experimental determination is mapped out.

Experimental structure determination used to have a very high failure rate and the money and time spent on failed attempts is a major contributor to the total expense and time needed to solve protein structures. Both can be significantly improved using “Big Data” approaches, as researchers learn from thousands of successful and failed experiments in structural biology. The SBP bioinformatics group uses these approaches to improve success rates at CSGID, allowing our center to solve more structures at lower costs.

Until recently the process of determining the 3D structure of a protein took many months or even years to complete, but advances in technology, such as the Advanced Photon Source, and upgrades to computational hardware and software has dramatically accelerated the process. The Seattle Structural Genomics Center for Infectious Disease, a similar center funded by NIAID, is also on track to complete 1,000 3-D protein structures soon. Browse all of the structures deposited by the CSGID.

Anyone in the scientific community interested in requesting the determination of structures of proteins from pathogens in the NIAID Category A-C priority lists or organisms causing emerging and re-emerging infectious diseases, can submit requests to the Center’s web portal. As part of the services offered to the scientific community, the CSGID can also provide expression clones and purified proteins, free of charge.

This project has been supported by federal funds from the NIAID, NIH,  Department of Health and Human Services, under contract numbers HHSN272200700058C and HHSN272201200026C.

Institute News

New grant supports Ebola drug discovery

AuthorJessica Moore
Date

March 24, 2017

Ebola’s reputation as a killer virus is well deserved—the most recent outbreak, in West Africa from 2014-2016, caused more than 11,000 deaths among 28,000 infections, according to the World Health Organization. Outbreaks have occurred regularly since 1976, so another is likely, but the timing is hard to predict. While an effective vaccine against the virus has been developed and will likely be approved, there are no drugs available to treat Ebola infections.

Ebola is not just deadly. It also causes an awful disease—sudden fever, fatigue, muscle pain, and headache that last for days, followed by vomiting and diarrhea that lead to severe dehydration, requiring IV fluids. Many Ebola patients also bleed internally and externally, from IV insertion sites, the nose and eyes.

A new $4.1 million grant from the National Institute of Allergy and Infectious Diseases supports research to find compounds that block the growth of Ebola virus, which could lead to new antiviral drugs. Sumit Chanda, PhD, professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), and Anthony Pinkerton, PhD, director of medicinal chemistry at SBP’s Conrad Prebys Center for Chemical Genomics, are collaborators on the effort. Christopher Basler, PhD, professor and director of the Center for Microbial Pathogenesis at Georgia State University, is directing the project.

“Drugs for Ebola are still urgently needed,” says Chanda. “Even with a vaccine, there’s still the possibility that someone who hasn’t been vaccinated might be exposed and carry it to an area where it’s not endemic.”

The SBP investigators will not be working with the disease-causing Ebola virus itself. Instead, they’ll be using non-infectious components, avoiding the need for special containment facilities.

The scientific team, which also includes Megan Shaw, PhD, associate professor at the Icahn School of Medicine at Mount Sinai, and Robert Davey, PhD, scientist at Texas Biomedical Research Institute, will first identify inhibitors of the viral machinery. Later phases of the project will confirm efficacy against live Ebola virus, determine how the drug candidates block the viral machinery and develop additional tests to identify drug candidates that will inhibit not only Ebola virus, but also the related Marburg virus.

“Marburg is also highly lethal,” says Pinkerton. “Drugs that work against the whole virus family would provide an even greater benefit to public health.”

This story was based in part on a press release from Georgia State University.