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 Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>