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  • richardmitnick 2:07 pm on June 16, 2017 Permalink | Reply
    Tags: , Flu Viruses, , ,   

    From Science: “Designer protein halts flu” 

    Science Magazine

    June 12, 2017
    Robert Service


    A designer protein (brown and orange) fits snugly on top of the influenza virus’s hemagglutinin protein (green), which helps the virus latch onto and infect cells.
    Eva-Maria Strauch

    There’s a new weapon taking shape in the war on flu, one of the globe’s most dangerous infectious diseases. Scientists have created a designer protein that stops the influenza virus from infecting cells in culture and protects mice from getting sick after being exposed to a heavy dose of the virus. It can also be used as a sensitive diagnostic. And although it isn’t ready as a treatment itself, the protein may point the way to future flu drugs, scientists say.

    “It’s impressive,” says James Crowe, an immunologist at Vanderbilt University in Nashville, who was not involved in the study. But because it hasn’t yet been tested in humans, “it [still] has a long way to go,” he says.

    Influenza severely sickens 3–5 million people each year, and it kills between 250,000 and 500,000, mostly the elderly and people with weakened immune systems. Every year, public health officials survey the three flu subtypes circulating in humans and design a vaccine for the next winter season that covers them all. But those vaccines are far from perfect: They don’t always exactly match the viruses actually going around, and in some people, the shots fail to trigger a vigorous immune response.

    Drugs are another line of defense. Most focus on the proteins on the virus’s outer coat, neuraminidase and hemagglutinin (HA). Some drugs that block neuraminidase, which helps the virus escape already infected cells, are starting to bump up against viral resistance. HA is scientists’ next target. The mushroom-shaped protein specializes in infecting cells, first by binding a trio of sites on its head to three separate sugar molecules on the surface of targeted cells. Once the virus latches on, parts of HA’s stem act as a grappling hook to pull the virus in close, allowing it to fuse with the cell membrane and release its contents inside.

    In 2011, researchers led by David Baker, a computational biologist at the University of Washington in Seattle, created a designer protein that binds HA’s stem, which prevented viral infection in cell cultures.

    Dr. David Baker, Baker Lab, U Washington

    But because the stem is often shrouded by additional protein, it can be hard for drugs to reach it.

    Now, Baker’s team has designed proteins to target HA’s more exposed head group. They started by analyzing x-ray crystal structures that show in atomic detail how flu-binding antibodies in people grab on to the three sugar-binding sites on HA’s head. They copied a small portion of the antibody that wedges itself into one of these binding sites. They then used protein design software called Rosetta to triple that head-binding section, creating a three-part, triangular protein, which the computer calculated would fit like a cap over the top of HA’s head group.

    Rosetta@home project, a project running on BOINC software from UC Berkeley

    My BOINC

    Next, they synthesized a gene for making the protein and inserted it into bacteria, which cranked out copies for them to test.

    In the test, Baker’s team immobilized copies of the protein on a paperlike material called nitrocellulose. They then exposed it to different strains of the virus, which it grabbed and held. “We call it flu glue, because it doesn’t let go,” Baker says. In other experiments, the protein blocked the virus from infecting cells in culture, and it even prevented mice from getting sick when administered either 1 day before or after viral exposure, they report today in Nature Biotechnology.

    Despite these early successes, Baker and Crowe caution that the newly designed protein isn’t likely to become a medicine itself. For starters, Baker says, the protein doesn’t bind all flu strains that commonly infect humans. That means a future drug may require either a cocktail of HA head group binding proteins or work in combination with stem-binding versions. Second, the safety of designer proteins will have to be studied carefully, Crowe says, because they are markedly different than natural HA-binding antibodies. “The further you get away from a natural antibody, the less you can predict what will happen,” Crowe says.

    But down the road, Baker says, the new designer protein could serve as the basis for a cheap diagnostic—akin to a pregnancy test—for detecting flu and possibly even medicines able to knock it out.

    See the full article here .

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  • richardmitnick 11:13 am on February 16, 2017 Permalink | Reply
    Tags: Flu Viruses, INTERCEPT program, Laura Fabris, , TIPs – therapeutic interfering particles,   

    From Rutgers: Women in STEM – “Attacking the Flu by Hijacking Infected Cells” Laura Fabris 

    Rutgers University
    Rutgers University

    February 16, 2017
    Todd B. Bates

    An influenza virus. Photo: Jezper/Shutterstock

    They’re called TIPs and their task would be to infiltrate and outcompete influenza, HIV, Ebola and other viruses.

    Soon, Rutgers’ Laura Fabris will play a key role in a project aimed at designing TIPs – therapeutic interfering particles to defuse the flu.

    Laura Fabris, associate professor in the Department of Materials Science and Engineering. Photo: Kate Woodside

    For the first time in virology, Fabris and her team will use imaging tools with gold nanoparticles to monitor mutations in the influenza virus, with unprecedented sensitivity, when it enters cells. Fabris will soon receive a $820,000 grant from the Defense Advanced Research Projects Agency (DARPA). It’s part of a four-year, $5.2 million INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program.

    Fabris’s work is beginning as New Jersey weathers a high rate of influenza activity this year.

    “Before we can understand how to make these therapeutic particles, we need to understand how viral mutation works,” said Fabris, an associate professor in the Department of Materials Science and Engineering.

    DARPA says it wants to harness TIPs – tiny virus-like entities with engineered genetic material that encodes defective viral proteins. TIPs, like viruses, can enter cells, but they don’t replicate unless the cells are also infected with the virus. RNA viruses like influenza are coated by a protein-studded membrane envelope, Fabris noted.

    In a cell infected with both a flu virus and a TIP, the cell makes copies of the TIP genome that compete for viral proteins. The goal is for harmless TIPs to outnumber flu virus genetic elements so infected cells would generate relatively few infectious viruses and a bumper crop of “dud viruses” with TIP genes, rapidly diluting the harmful viruses and halting the infection, according to DARPA.

    In preliminary studies funded by DARPA, TIPs in cells grown in culture dishes slashed viral counts by nearly 20-fold. But the INTERCEPT program, seeking enhanced anti-viral performance, will support testing of TIP safety and effectiveness in animal models, DARPA says. It also seeks to determine whether TIPs, through spontaneous mutations, can keep up with new tricks that viruses may develop while evolving.

    The INTERCEPT program features a multidisciplinary team of virologists, evolutionary biologists, mathematicians and materials scientists from North Carolina State University (Ruian Ke), Duke University (Katia Koelle), University of Illinois at Urbana-Champaign (Christopher Brooke), Montana State University (Connie Chang), and Rutgers. The focus is on discovering how the influenza virus mutates at the cellular, animal and population levels, said Fabris, who works in the School of Engineering. One goal is to predict whether TIPs will keep up with flu virus mutations.

    “Ideally, the TIPs will be introduced into influenza virus populations and compete for protein, so the virus will starve and not be able to reproduce,” she said.

    Her role will be to provide imaging and quantification methods to study, in cells and eventually animals, which parts of the influenza virus genome have mutated and to what degree. It will be the first time that surface enhanced Raman scattering, which measures vibrations in molecules and therefore reports on their chemical composition and structure, will be used in virology, she said.

    Each molecule has a unique vibration frequency, and complex molecules have complex vibration patterns, said Fabris, who began using the technique 11 years ago.

    She and her team will use gold nanoparticles to examine and quantify the nanoparticles inside cells. She uses gold nanoparticles because they localize the light similarly to a lens and enhance the observed signal intensity.

    “Our research will have repercussions, for example, in how to do sequencing of genes in a way that is cheaper and deeper compared with traditional sequencing,” Fabris said.

    See the full article here .

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  • richardmitnick 5:52 pm on December 8, 2014 Permalink | Reply
    Tags: , , Flu Viruses, ,   

    From SLAC: “Study May Help Slow the Spread of Flu” 

    SLAC Lab

    December 8, 2014

    X-rays Show How Flu Antibody Binds to Viruses

    An important study conducted in part at the Department of Energy’s SLAC National Accelerator Laboratory may lead to new, more effective vaccines and medicines by revealing detailed information about how a flu antibody binds to a wide variety of flu viruses.

    A false color image of an influenza virus particle, or “virion.” (Centers for Disease Control/Cynthia Goldsmith)

    The flu virus infects millions of people each year. While for most this results in an unproductive and uncomfortable week or two, the flu also contributes to many deaths in the average flu season. And while vaccines are effective in preventing the flu, they require almost yearly reformulation to keep up with the constantly changing virus.

    A team of researchers from The Scripps Research Institute, Fujita Health University and Osaka University studied both samples of flu virus components and an anti-flu antibody. The antibody, called F045-092, was already known to neutralize the flu by connecting to the region of the flu virus that binds to host cells, so it can no longer bind to its target and cause infection.

    Top: The antibody F045-092 inserts a loop (purple) into the region of the flu virus (blue) that would otherwise bind to host cells to initiate infection. With the antibody connected, the flu virus is unable to bind to its target and cannot cause infection. Bottom: Without the antibody present, the flu virus (blue) binds to a host cell receptor (yellow). (Peter Lee et al.)

    “There are patches of the virus that are more hypervariable than others,” said Peter Lee, a postdoctoral research associate at The Scripps Research Institute and first author of the paper. “But the flu always binds to host cells within the same region, and so that binding site needs to be functionally conserved. That makes it a site of vulnerability.”

    The team used the X-ray beams at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) and Argonne National Laboratory’s Advanced Photon Source (APS), both DOE Office of Science User Facilities, to view the structure of the antibody bound to one subtype of the flu virus called H3N2. They discovered that the antibody inserts a loop into the binding site of the virus, which would otherwise attach to a receptor in a host cell. Additional experimental data showed that F045-092 binds a wide variety of strains and subtypes, including all H3 avian and human viruses from 1963 to 2011 that were tested.

    SSRL at SLAC

    ANL APS interior
    Argonne National Laboratory’s Advanced Photon Source

    This understanding of the antibody’s structural details and binding modes offers new insight for future structure-based drug discovery and novel avenues for designing future vaccines.

    But the only way to achieve those goals is for many groups of scientists to work together, Lee said. “Our lab is very focused on the structure of the virus and antibodies, while there are lots of other labs focused on everything from small protein design to vaccine design,” he said. “Hopefully we can use this structural information and join together as one big team to tackle the flu.”

    SSRL’s Structural Molecular Biology program is supported by the National Institutes of Health and the Office of Biological and Environmental Research of the U.S. Department of Energy.

    See the full article here.

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    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

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