17-May-2022 - Friedrich Miescher Institute for Biomedical Research

Thwarting cellular enzyme can fight viral infections

The findings could help to develop drugs that combat viruses such as influenza A and Zika

FMI researchers have identified a synthetic protein that dampens the activity of a cellular pathway involved in viral infection. The findings could help to develop drugs that combat viruses such as influenza A and Zika.

Influenza A virus affects millions of people worldwide and can have serious complications, including bacterial pneumonia, ear infections and the worsening of long-term medical conditions.

Once the flu virus enters a cell in the body, it has to release its genetic material, which is packed into a protein shell called capsid. To do so, the virus hijacks some of the molecular machinery of the cell: loosely attached to the virus are chains of a protein called ubiquitin, which interacts with a cellular enzyme known as HDAC6; at the same time, HDAC6 binds to components of the cell’s skeleton and to motor proteins, pulling the capsid into pieces so that it can be degraded by the cell’s waste disposal machinery. Opening up the capsid releases the genetic material of the virus inside the cell, facilitating viral infection.

To test whether interfering with HDAC6’s interaction with ubiquitin could hinder flu infection, Longlong Wang and his colleagues in the Matthias group screened DARPins, a class of synthetic proteins that can bind to a variety of targets. The researchers found one DARPin that was able to latch onto HDAC6 and prevent it from binding to ubiquitin, in both test tubes and cells grown in a dish. Cells expressing this DARPin showed reduced levels of infection not only with influenza A but also with Zika virus. Zika virus, which is spread through mosquito bites, causes a disease that in pregnant women can lead to stillbirth or birth defects such as smaller-than-average head and brain.

The findings, published in Cell Reports on April 26, suggest that HDAC6’s binding to ubiquitin is an attractive target for drug discovery, and preventing this binding could help fight infections with viruses such as influenza A and Zika.

Viruses rapidly accumulate mutations, which could confer resistance to antiviral drugs, says senior study author Patrick Matthias. For this reason, he adds, scientists are interested in targeting cellular pathways like the one his team has targeted. “We have very few drugs against viruses, so there is room for progress in the future.”

Facts, background information, dossiers
More about Friedrich Miescher Institute for Biomedical Research
  • News

    A new mechanism for accessing damaged DNA

    UV light damages the DNA of skin cells, which can lead to skin cancer. But this process is counteracted by the DNA repair machinery, acting as a molecular sunscreen. It has been unclear, however, how repair proteins work on DNA tightly packed in chromatin, where access to DNA damage is rest ... more

    Clues to making drugs for "undruggable" targets

    Nicolas Thomä's group at the FMI has joined forces with the group of Benjamin Ebert at Harvard’s Broad Institute to show how thalidomide analogs mediate degradation of many more proteins than previously anticipated. These proteins – zinc finger transcription factors – play a role in cancer ... more

    Controlling cell-fate decisions

    Rafal Ciosk and his group at the FMI have identified an important link between the Notch signaling pathway and PRC2-mediated gene silencing. They showed that a fine balance between epigenetic silencing and signaling is crucial for cell-fate decisions. While this study has important implicat ... more

  • Research Institutes

    Friedrich Miescher Institute for Biomedical Research

    The Friedrich Miescher Institute is devoted to fundamental biomedical research aimed at understanding the basic molecular mechanisms of health and disease. We communicate and patent our findings to enable their translation into medical application. The FMI focuses on the fields of Epigeneti ... more