Penn Researchers Discover Key to How SARS Virus
Inhibitors of Cellular Enzymes Could Be Developed For SARS Treatment
(Philadelphia, PA) - 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
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. (Click on
thumbnail to view full-size images). 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
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
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.
Co-authors are Dhaval N. Gosalia, Andrew J. Rennekamp, and Jacqueline
D. Reeves, all from Penn. This study was funded by NIH and the NIH Mid-Atlantic
Regional Center of Excellence for Biodefense and Emerging Infectious Diseases.
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