Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn researchers discover key to how SARS virus infects cells

02.08.2005


Inhibitors of cellular enzymes could be developed for SARS treatment



Researchers from the University of Pennsylvania School of Medicine have found that inhibitors of an enzyme called cathepsin L prevent the SARS (severe acute respiratory syndrome) virus from entering target cells. SARS is caused by an emergent coronavirus. There is no effective treatment at this time.

This study also demonstrates a new mechanism for how viral proteins are activated within host cells, states senior author Paul Bates, PhD, an Associate Professor in the Department of Microbiology. Bates and first author Graham Simmons, PhD, Research Associate, also in the Department of Microbiology, published their findings in the early August issue of the Proceedings of the National Academy of Sciences.


To gain entry, a virus binds to receptors on the surface of the host cell, and is taken up into a vesicle, or sphere, inside the cell. Unlike most known viruses, the SARS coronavirus (like the Ebola virus) needs one more step to infect the cell. The proteins within the membrane of both SARS and Ebola need to be cut by special cellular enzymes (cathepsins) in order to replicate within the host cell. Cathepsins act in the low pH (acidic) environment inside the vesicle, facilitating fusion of the viral membrane and the vesicle membrane, so that viral proteins and nucleic acids can enter the cell where viral replication occurs.

"This paper changes the thinking of the field," says Bates. "Up to this point, everyone thought all of the activation steps were at the cell surface or due to the low pH environment in the vesicle. Our paper shows that it’s not just low pH, but the cathepsin proteases in the vesicles that clip the viral protein. This gives us a new target to address in the development of therapeutics against the SARS virus."

The researchers found that several chemical inhibitors of cathepsin activity blocked infection of human cell lines by the SARS virus, which were grown in a high-level safety laboratory. In general, these findings, say the researchers, have led to a better understanding that the cutting of viral protein by cathepsins is necessary for infectivity and is likely not unique because both the SARS and Ebola viruses are now known to use a similar mechanism to invade their host cells. (In June 2005, a group from Harvard School of Medicine discovered that the Ebola viral membrane protein is similarly activated by cathepsin L and B.)

If these proteases are important for other viruses, they represent a new way to stop viral infection. SARS and Ebola are the first examples of the need for these proteins to be cleaved during infection of the host cell.

This work is a joint collaboration between the Bates lab and the research group led by Scott L. Diamond, PhD, Director of the Penn Center for Molecular Discovery, one of nine facilities that the National Institutes of Health (NIH) is establishing as part of the Molecular Library Screening Center Network. Diamond is also Professor of Chemical and Biomolecular Engineering within the Institute for Medicine and Engineering at Penn. While independently screening for inhibitors, Diamond’s lab found a cathepsin L inhibitor called MDL28170, which Bates and Simmons tested for efficacy in inhibiting SARS coronavirus infection. The cellular cathepsin enzymes have many other roles within the body, including mediating the inflammatory immune response in the lungs and antigen processing in T cells.

The Bates research group, in collaboration with the Diamond group, has identified a few compounds, including MDL28170, which they plan to test in animals for SARS inhibition. "We’re now searching for other viruses that also use this cleaving mechanism for activating their proteins," says Bates. "If there are a number of other viruses that do that, and we have some preliminary evidence to suggest this, then we can develop small molecule inhibitors as possible therapeutics." One advantage of this approach is that oral medications made from small-molecule inhibitors are more readily made and distributed in the developing world-as opposed to a vaccine, suggests Bates. Protease inhibitors active against cathepsins have been tested in mice with no ill side effects, which bodes well for their eventual testing in humans.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences

nachricht The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Previous evidence of water on mars now identified as grainflows

21.11.2017 | Physics and Astronomy

NASA's James Webb Space Telescope completes final cryogenic testing

21.11.2017 | Physics and Astronomy

New catalyst controls activation of a carbon-hydrogen bond

21.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>