Synthetic heparanase inhibitors inhibit the spread of herpes viruses in tissue
Herpes is not only unpleasant but it can, in some cases, also have
dangerous complications and life-threatening consequences. In the
journal Angewandte Chemie, a research team has now introduced a
completely new approach for treating herpes. Their method is based on
the inhibition of an enzyme that is needed for the release of newly
formed virus particles from infected cells.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Just before an important interview or anticipated first date—always
when you least need it—you feel a tingling and itching on your lip. A
glance in the mirror reveals the first little blisters: herpes is back.
The majority of adults carry the instigator in their bodies because,
once infected, herpes simplex Type 1 viruses (HSV-1) settle into nerve
ganglia. They remain in the body throughout a person’s life, inactive
most of the time. If the immune system is temporarily weakened, maybe by
anxiety or stress, too much sunlight, hormonal fluctuations, or a cold,
an outbreak may occur. This is annoying and painful but usually
harmless. However, this is not always the case: in some
immunocompromised individuals or newborns there can be severe and
sometimes life-threatening consequences. Dangerous complications are
also a threat if the virus infects the eyes or brain; for example,
corneal herpes is one of the leading causes of infection-induced
blindness. Antiviral drugs can curb herpes infections but not fully
vanquish them.
A team from the University of Georgia, Athens (USA), the University
of Illinois at Chicago (USA), and the University of Utrecht
(Netherlands), led by Deepak Shukla and Geert-Jan Boons, has now
developed an alternative method for the treatment of herpes.
HSV-1 viruses dock to heparan sulfates, molecules that are made of
many sugar (saccharide) units and are found in the extracellular matrix
and plasma membranes of our cells. Once bound, the viruses can enter the
cells. In the late stages of infection the virus causes the infected
cells to increase production of heparanase, an enzyme involved in the
remodeling of the extracellular matrix. It splits heparan sulfates off
the surface of the cell—a prerequisite for the release of the viruses
newly produced in the cell so that they can spread to other cells and
tissues. The idea behind this project is to block the heparanase.
The team synthesized a series of oligosaccharides that have
structures like those of heparan sulfates but are not split by the
heparanase enzyme. Molecules made of six or eight saccharides strongly
inhibit heparanase. By using complementary computer studies, the team
was able to model the way these oligosaccharides are arranged in the
enzyme’s binding cavity and determine which molecular interactions are
responsible for the strong binding. Treatment of corneal cells infected
with HSV-1 with the active oligosaccharides had the effect of inhibiting
the virally induced excretion of heparan sulfates, significantly
reducing the spread of the virus.
In addition, inhibition of heparanase through the new inhibitors can
impede the migration and proliferation of immortalized cells (that is,
cells with uncontrolled cell growth). This enzyme has been strongly
implicated in cancer metastasis, suggesting another potential
application for the inhibitors in the future.
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About the Author
Geert-Jan Boons is
the UGA Foundation Distinguished Professor in Biochemical Sciences at
the Department of Chemistry and the Complex Carbohydrate Research Center
(CCRC) of the University of Georgia (USA), and Professor and Chair of
the Department of Medicinal and Biological Chemistry of Utrecht
University (The Netherlands). His group is developing methods for
synthesizing complex glycans and glycoconjugates that are being used for
biological and biomedical explorations with a focus on infectious
diseases, immunology, and cancer.
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