World wide, over 240 million people
are infected with Hepatitis B (HBV), a liver cell infecting virus capable of
causing degeneration, such as cirrhosis, and cancers such as hepatocellular
carcinoma. Unlike HIV or Hepatitis C infections, which carry the genetic code
for about 10 viral proteins, HBV only carries four genes, making it very
difficult to target with drug treatment. Two broad categories of antiviral
treatment do exist for HBV infections, nucleoside analogs, which block the
viruses ability to translate its genes in to proteins and replicate, and
interferon’s, which amplify the body’s immune response to the virus presence.
Unfortunately, these treatment options both have drawbacks like causing the
development of drug resistant viruses and intolerable side effects for the
infected patient. Because combining antiviral treatments has been shown to be
very effective in managing infections such as HIV, it is important today for
researchers to identify safe molecules with novel antiviral inhibition modes.
Recently, researchers at the National Institute of Infectious disease in Tokyo,
Japan have found that a chemical called proanthocyanidin has shown strong
potential in inhibiting Hepatitis B and Hepatitis D infection both alone and in
conjunction with a commonly used nucleoside analog.
Proanthocyanidin,
referred to here as PAC, is a chemical found in grape seed extract that is made
up of multiple flavonoid units. Through screening many molecules, researchers
were able to identify PAC for its ability to inhibit HBV infection. After
identification of its inhibitory quality, researchers pressed on to answer some
important questions regarding PAC’s mode of inhibition. First, researchers
studied what step of the viral replication cycle PAC disturbed, then what
host-virus interaction it affected, whether PAC interacted with liver
hepatocytes or HBV virions, which specific region of the host or virus receptor
PAC interacted with, and finally how PAC performed as antiviral therapy when
combined with a nucleoside analog. The results they found offered a very
promising outlook for PAC as a non-toxic antiviral treatment option that works
through a novel mechanism.
The LHB membrane protein found on the surface of Hepatitis B. This protein is responsible for binding to the NCTP receptor on hepatocytes and facilitating viral entry. |
Through
numerous chemical tests performed in cell cultures that mimicked the human liver,
researchers deduced that PAC and related analogs interact with a specific 7
amino acid sections in the preS1 region of a large protein found on the virus
envelop surface. This interaction prevented the viral protein LHB from binding
to hepatocyte receptors, thus preventing viral entry necessary for productive
infection. Researchers first determined that PAC prevented virus entry by
treating cell cultures with PAC before infection and after infection. The
results showed that only cells treated before introduction of virus avoided
infection. By inferring the method of entry inhibition from previously
identified, yet toxic antiviral molecules, the researchers were able to design
a chemical test to specifically monitor the interaction of the LHB preS1 domain
and its cell receptor counterpart, a sodium dependent bile uptake protein
(NTCP) found on the liver cell surface. The introduction of PAC to this system
prevented the specific interaction between LHB and NTCP. Researchers questioned
which side of the LHB-NTCP interaction PAC was inhibiting. They were able to
answer this question by infecting culture cells previously treated with PAC and
infecting culture cells with viral particles previously treated with PAC. The
results showed that viral particles treated with PAC before being introduced to
cells showed limited capacity to infect, whereas cells treated with PAC were
still susceptible to infection. Finally, by introducing mutations to the preS1
domain of the viral protein LHB responsible for receptor binding and virus
particle entry, researchers were able to locate PAC-preS1 interactions to amino
acids 9-16. Taken together this study showed that PAC works as a
viral-entry-inhibiting-molecule that prevents the preS1 domain, specifically
amino acids 9-16, of envelop protein LHB from binding to the NTCP receptor
found on hepatocytes, and thus prevents viral particles from entering cells and
infecting them.
As
an antiviral treatment, PAC and its analogs have been shown to safely inhibit viral
infection in both HBV and HDV, and to work effectively in conjunction with
nucleoside analogs to manage infection. In tests with tenofovir, a nucleoside
analog used to treat HBV, PAC was shown to inhibit viral production and spread
of infection without any toxic effect for cells. This result has important
implications for multidrug treatment, as PAC works to affect viral particles
through a novel inhibition pathway. PAC is also a naturally occurring molecule
that is already found in supplements of grape seed extract at concentrations
high enough to exhibit its antiviral properties. This is a very significant
finding for the millions of people currently infected with HBV looking to
manage infection and people at risk of contracting an HBV infection as it is
readily available, safe to ingest daily, and cost effective as it does not
require chemical synthesis. While this work is very promising, PAC has not been
confirmed to effectively interact with virus cells in live humans. This means
that the most important research that needs to be carried out in the future is
studies of the effectiveness of PAC and its derivatives at inhibiting viral
infection and spread in live organisms rather than cell culture.
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