WHO declares that dengue is
one of the
fastest-emerging
infections in the world, [but research focus and funding have decreased].
DENGUE fever and dengue hemorrhagic
fever (DHF) are diseases caused by a family of viruses that are transmitted by
mosquitoes. Dengue viruses infect nearly 100 million people each year in more
than 100 countries. Seventy percent of these come from the Asia-Pacific. WHO
said "much of Asia continues to be in the grip of dengue fever, with the
number of hospitalizations and severe cases growing." Some countries have
reported significant increases in dengue outbreaks as compared to the same
period last year. Among the badly affected countries cited are the Philippines,
Lao People's Democratic Republic, Malaysia, and Vietnam.
Dengue hemorrhagic fever
(DHF) is a more severe form of the viral illness. Manifestations include
headache, fever, rash, and evidence of hemorrhage in the body. Small red or
purple blisters under the skin, bleeding in the nose or gums are all possible
signs of hemorrhage. This form of dengue fever can be life-threatening and can
progress to the most severe form of the illness, dengue shock syndrome (DSS). The mortality (death) rate with DHF is
significant. It ranges from 6%-30%. Most deaths occur in children.
The dengue virus (DENV)
The disease is caused by four closely related virus serotypes of the
genus Flavivirus, family Flaviviridae.
Each serotype is sufficiently different that
there is no cross-protection and epidemics caused by multiple serotypes can
occur. Dengue is transmitted to humans by the Aedes aegypti mosquito. Because it is caused by one of four
serotypes of virus, it is possible to get dengue fever multiple times. However,
an attack of dengue produces immunity for a lifetime to that particular
serotype to which the patient was exposed.
How dengue virus
invades a cell
Dengue
is an enveloped virus, which means it's surrounded by a protein layer and a
lipid bilayer. Inside this viral envelope is a protein coat called a capsid,
and the RNA genome. To infect a host cell, the dengue virus must find a way to
penetrate the cell's plasma membrane.
Dengue virus enters a host cell when the
viral envelope glycoprotein, E, binds to a receptor. Its major envelope glycoprotein, E, mediates viral attachment and
entry by membrane fusion. A crystal structure of the soluble domain of E from
dengue virus type 2 reveals a hydrophobic pocket lined by residues that
influence the pH threshold for fusion. The pocket, which accepts a hydrophobic
ligand, opens and closes through a conformational shift in a beta-hairpin at
the interface between two domains. Once inside, it must find a way to fuse yet
another cellular membrane—the host cell's endosomal membrane—with its own so
that the virus' RNA cargo can be released.
This visualization adapted from the University of
Massachusetts Medical School represents the process by which a dengue virus
releases its genetic contents inside a host cell, allowing viral replication.
The key players are proteins found on the viral surface called envelope
proteins, which change their structure when the virus is endocytosed, or taken
inside the cell. This structural change enables the viral membrane to fuse with
the endosomal membrane, and the virus' RNA to enter the cytoplasm of a host
cell. There, ribosomes will make viral proteins that will spread to other cells
through the replication and secretion of new viral particles.
Treatment for dengue fever
Because dengue fever is caused by a virus, there is no specific
medicine or antibiotic to treat it. There are no available vaccines or
antivirals against DENV. Currently, vector control is the only method for
prevention of the disease. Development of a successful vaccine would require
for it to be effective against all four DENV serotypes, economical, and provide
long-term protection. For typical dengue, the treatment is purely concerned
with relief of the symptoms (symptomatic). Rest and fluid intake for adequate
hydration is important. Aspirin and nonsteroidal anti-inflammatory drugs should
only be taken under a doctor's supervision because of the possibility of worsening
hemorrhagic complications. Paracetamol, acetaminophen and codeine may be given
for severe headache and for the joint and muscle pain.
Dengue cases are
increasing
The WHO pointed out a number of factors that have caused the
increase in dengue cases around the world. These include higher temperatures
and rainfall, growing population densities, and greater international travel.
So far, there is no firm evidence that points out global warming as the
ultimate culprit, climate change has played an important role. Because of
climate change, mosquitoes are now found in areas where they were once
uncommon. Dengue may also be transmitted via infected blood products and in
countries such as Singapore, where dengue is endemic, the risk was estimated to
be between 1.6 and 6 per 10,000 blood transfusions.
Current research efforts
on dengue
A health problem of this scope should be regarded as high priority
and should have attracted ample funding from donors and national authorities.
But such is not the case. Historical review reveals that there is a greater
number of laboratories and a greater allocation of resources to dengue research
30-50 years ago than there is today.
Molecular replication mechanism of the DENV.
In 2006 a group of Argentine scientists discovered the molecular
replication mechanism of the virus, which could be specifically attacked by
disrupting the viral RNA polymerase.
“At first we were puzzled by the cyclization feature of this virus.
We now recognize that it serves a role in bringing the promoter near the
initiation site”, a statement from Andrea V. Gamarnik, a virologist from Leloir
Institute Foundation in Buenos Aires. They have described how a viral enzyme
recognizes and amplifies the genetic material needed to assemble new dengue
viruses. Their findings provide the first model for RNA replication in the
family of viruses that includes West Nile, St. Louis encephalitis, and
hepatitis C.
Molecules as inhibitors to stop replication.
Other studies are working on the search of possible small molecules
that can bind at the ligand-binding pocket present in the dengue virus. The
binding of such molecule can act as inhibitors to stop infection.
Further research done
by this group
proposed a fusion mechanism driven by essentially irreversible conformational
changes in the viral envelope glycoprotein, E, and facilitated by fusion-loop
insertion into the outer bilayer leaflet. Specific features of the folded-back
structure suggest strategies for inhibiting flavivirus entry.
Another study involving dengue drug
discovery is trying to develop drugs that inhibit the viral
NS3 protease. The NS3 protease is an enzyme critical for virus replication, and
its amino acid sequence and atomic structure are very similar among the
different disease–causing flaviviruses. Since the atomic structure of the NS3
protease is known, we can utilize advanced structure–based computational drug
discovery methods to identify small molecule protease inhibitors. Dr. Stan Watowich and his research
team at The University of Texas Medical Branch (Galveston, Texas, USA) have
made significant progress in this direction, having discovered compounds that
inhibit dengue and West Nile virus proteases and prevent virus replication in
cell culture. However, additional drug candidates need to be discovered to
improve the likelihood of converting drug leads into approved drugs for
treating flavivirus infections.
Recently, the company,
NanoViricides, Inc. developed a library of chemical ligands that are expected
to bind to the dengue virus envelope proteins of several different subtypes of
dengue viruses. These ligands were developed using the results of
sophisticated, well established, molecular modeling software. A number of candidate
nanoviricides that are capable of attacking the dengue virus were created using
these ligands. A "nanoviricide" is a chemical substance made by
covalently attaching a number of copies of a virus-binding ligand to a base
polymeric micelle, that the Company calls TheraCour®. It is believed that when
a nanoviricide binds to a virus particle, the interaction would extend to the
binding of a large number of ligands to the virus surface, and the flexible
nanomicelle would then engulf the virus, rendering it incapable of infecting a
cell.
Cited
Literature
Modis, Y., Ogata, S.,
Clements, D. & Harrison, S.C. Structure of the dengue virus envelope
glycoprotein after membrane fusion. Nature, 427: 313-319 (2004).
Kuhn RJ, Zhang
W, Rossmann MG, et al. Cell 2002, 108:717-725.
Modis, Y., Ogata, S.,
Clements, D. & Harrison, S.C. A ligand-binding pocket in the dengue virus
envelope glycoprotein. PNAS, 100, 12: 6986-6991 (2003).
World Health Organization (on dengue).
Can be accessed at <www.who.int> by searching dengue or
dengue virus. Last accessed: October 6, 2010.
WHO Dengue and dengue hemorrhagic fever
Fact Sheet No. 117, March 2009
Medicinenet (on dengue). Can be accessed at <www.medicinenet.com>
by searching dengue or dengue virus. Last accessed: October 7, 2010.
The Medical News
<news-medical.net>. Anti-dengue drug candidates demonstrate efficacy in
preliminary cell culture studies. June
2010.