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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 11, 2009
Contents
New Developments in Drug and Vaccine
Discoveries
Executive Editor: Aldar S. Bourinbaiar
Editorial: Pp. 1157-1158
Clinical Experience with Therapeutic Vaccines Designed for
Patients with Hepatitis Pp. 1159-1171
D. Batdelger, D. Dandii, Y. Dahgwahdorj,
V. Jirathitikal and A.S. Bourinbaiar
[Abstract] [Purchase
Article] [PMID: 19355957 PubMed - indexed for MEDLINE]
Design of Iodine-Lithium-α-Dextrin
Liquid Crystal with Potent Antimicrobial and Anti-Inflammatory
Properties Pp. 1172-1186
T.K. Davtyan, L.M. Mkhitaryan and
E.S. Gabrielyan
[Abstract] [Purchase
Article] [PMID: 19355958 PubMed - indexed for MEDLINE]
Novel Inhibitors of HIV Discovered Among
Existing Classes of Pharmaceutical Compounds Indicated for
Unrelated Clinical Indications Pp. 1187-1190
I.I. Kucherov, P.G. Rytik, I.A. Podol’skaya,
L.O. Mistryukova and M.O. Korjev
[Abstract] [Purchase
Article] [PMID: 19355959 PubMed - indexed for MEDLINE]
The Gut Mucosa as a Site for Induction
of Regulatory T-Cells Pp. 1191-1202
M. Mizrahi and Y. Ilan
[Abstract] [Purchase
Article] [PMID: 19355960 PubMed - indexed for MEDLINE]
Attenuated D2 16681-PDK53 Vaccine: Defining
Humoral and Cell Mediated Immunity Pp. 1203-1211
J. Rabablert and S. Yoksan
[Abstract] [Purchase
Article] [PMID: 19355961 PubMed - indexed for MEDLINE]
Inhibition of Transcription Factors by
Plant-Derived Compounds and their Implications in Inflammation
and Cancer Pp. 1212-1237
J.L. Ríos, M.C. Recio, J.M. Escandell
and I. Andújar
[Abstract] [Purchase
Article] [PMID: 19355962 PubMed - indexed for MEDLINE]
Synthetic and Natural Immunomodulators
Acting as Interferon Inducers Pp. 1238-1247
D.S. Silin, O.V. Lyubomska, F.I. Ershov,
V.M. Frolov and G.A. Kutsyna
[Abstract] [Purchase
Article] [PMID: 19355963 PubMed - indexed for MEDLINE]
The Common Mycobacterial Antigens and
their Importance in the Treatment of Disease Pp.
1248-1260
J. Stanford, C. Stanford, G. Stansby, O.
Bottasso, G. Bahr and J. Grange
[Abstract] [Purchase
Article] [PMID: 19355964 PubMed - indexed for MEDLINE]
Desferrioxamine as Immunomodulatory Agent
During Microorganism Infection Pp. 1261-1268
A. Williams and D. Meyer
[Abstract] [Purchase
Article] [PMID: 19355965 PubMed - indexed for MEDLINE]
Antiviral Role of Toll-Like Receptor-3
Agonists Against Seasonal and Avian Influenza Viruses Pp.
1269-1274
J.P. Wong, M.E. Christopher, S. Viswanathan,
X. Dai, A.M. Salazar, L. Q. Sun and M. Wang
[Abstract] [Purchase
Article] [PMID: 19355966 PubMed - indexed for MEDLINE]
Abstracts
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Editorial: New Developments in Drug and Vaccine Discoveries
This special issue of “Current Pharmaceutical
Design” covers a broad range of topics with the unifying
theme – novel approaches to conquer a disease and improve
well-being of a patient. Most, if not all of these, are approaches
that already have passed the preclinical stage and have been
applied in clinical practice. In order to assemble this issue
the Editor picked original investigators working all over
the world in order to make it truly international and to provide
a representative sample of projects that are undertaken on
a global scale. The individual topics of this issue cover
every major global disease. The articles in this issue are
listed in the alphabetical order according to the surname
of the first author.
The team of Batdelger et al. [1] from Mongolia, Thailand
and USA, review the current trend in therapeutic vaccines
and summarize their own contribution to immunotherapy of hepatitis
B and C – two most common serious, infectious diseases
that affect globally over 500 million people or roughly 10%
of global population.
AIDS is another global disease affecting 30 million people.
Armenian group of Davtyan et al. [2] describe their
own approach to combat AIDS – an anti-inflammatory as
well as antiviral combination therapy that they have successfully
developed and applied in their own country.
Kucherov et al. [3] from Belarus describe results
of their drug screening effort for potential anti-HIV agents
among affordable, locally-manufactured drugs that have been
used for unrelated diseases. As a result they were able to
discover six new compounds, three of which can be deployed
immediately since they have been used safely by physicians
for other clinical conditions.
Immunologists Mizrahi and Ilan [4] from Israel offer us insight
into regulatory T lymphocytes (Tregs) and mucosal immunity.
They have applied in clinical practice the principle of oral
tolerance as a way to treat multiple immune disorders ranging
from hepatitis to inflammatory bowel disease. Each year, hundreds
of millions of dollars are devoted to researching the mysteries
of autoimmune diseases. Ilan and his team may have the answer
to that.
Thai scientists Rabablert and Yoksan [5] give us the account
of their long-standing effort to develop a vaccine against
dengue virus – the most important mosquito-borne viral
disease affecting humans. Its global distribution is comparable
to that of malaria. Tens of millions of cases of dengue infections
occur and, depending on the year, up to hundreds of thousands
of cases of dengue fever are reported with fatality rate about
5%.
Rios et al. [6] from Spain go back to roots of modern
pharmacology – medicinal herbs. Even today compounds
discovered from botanical sources constitute the backbone
of up to 25% of modern pharmacopoeia. Their review provides
an excellent source of promising targets for designing new
active drugs against inflammation and cancer.
Silin et al. [7] provide us with overview of clinically
deployed immune modulators that induce endogenous interferon.
Interferon is the first ever discovered immunomodulatory substance
that has been shown to display a wide range of activities
due to their antiviral, antibacterial, anti-tumor, and anti-inflammatory
properties. Despite the fact that inducers of interferon are
virtually unknown outside of the former Soviet Union and Eastern
European countries, they represent a substantial market share
of pharmaceutical drugs in that region.
Tuberculosis (TB) is another global disease that threatens
the world. In 2006, an estimated 1.7 million people died from
TB. Annually there are 9.2 million new cases of TB, and the
global prevalence of TB infection is one-third of the world’s
population – more than 2 billion people carrying the
TB bacteria could benefit from the protective and therapeutic
effects of Mycobacterium vaccae – a vaccine
that has been discovered and reviewed in this issue by Stanford
et al. [8].
Sub-Saharan Africa is burdened with HIV and Mycobacterium
tuberculosis more than the rest of the world. Wiliams
and Meyer [9] from the University of Pretoria in South Africa
review the role for iron chelators such as desferrioxamine
as inexpensive and effective immunomodulators that could be
useful for treatment of these microorganisms. Incidentally,
their research subject appears to connect with findings of
science team from Belarus who discovered anti-HIV property
of ferrous compound - Tardiferon.
Wong et al. [10] from the Canadian Army R&D
institution and his collaborators from USA and China describe
their work on agonists of Toll-like receptor-3 as an approach
that can help to counter seasonal and avian influenza viruses.
Seasonal influenza virus remains a serious public health threat
and highly pathogenic bird flu virus can potentially wipe
out the entire human population. Even though preventive vaccines
are available they do not confer full protection and for this
reason the development of innovative therapeutic approaches
needs to be continued.
It is hoped that topics discussed in this issue will be of
interest and reader may be intellectually enriched by new
ideas and approaches to overcome diseases that affect the
global community. Globalization is a trend that we are witnessing
now in every aspect of our life. This issue brought together
investigators from Argentina, Armenia, Belarus, Canada, China,
Israel, Lebanon, Mongolia, Russia, South Africa, Spain, Thailand,
UK, Ukraine and USA as a truly international contribution
aimed to provide practical solutions to health problems of
the world.
References
[1] Batdelger D, Dandii D, Erdentsogt H, Jirathitikal V, Bourinbaiar
AS. Clinical experience with therapeutic vaccines designed
for patients with hepatitis. Curr Pharm Des 2009; 15(11):
1159-1171.
[2] Davtyan TK, Mkhitaryan LM, Gabrielyan ES. Design of iodine-Lithium-α-dextrin
liquid crystal with potent antimicrobial and anti-inflammatory
properties. Curr Pharm Des 2009; 15(11): 1172-1186.
[3] Kucherov II, Rytik PG, Podol’skaya IA, Mistryukova
LO, Korjev MO. Novel inhibitors of HIV discovered among existing
classes of pharmaceutical compounds indicated for unrelated
clinical indications. Curr Pharm Des 2009; 15(11): 1187-1190.
[4] Mizrahi M, Ilan Y. The gut mucosa as a site for induction
of regulatory T-cells. Curr Pharm Des 2009; 15(11): 1191-1202.
[5] Rabablert J, Yoksan S. Attenuated D2 16681-PDK53 vaccine:
defining humoral and cell-mediated immunity. Curr Pharm Des
2009; 15(11): 1203-1211.
[6] Ríos JL, Recio MC, Escandell JM, Andújar
I. Inhibition of transcription factors by plant-derived compounds
and their implications in inflammation and cancer. Curr Pharm
Des 2009; 15(11): 1212-1237.
[7] Silin DS, Lyubomska OV, Ershov FI, Frolov VM, Kutsyna
GA. Immunomodulators acting as interferon inducers. Curr Pharm
Des 2009; 15(11): 1238-1247.
[8] Stanford J, Stanford C, Stansby G, Bottasso O, Bahr G,
Grange J. The common mycobacterial antigens and their importance
in the treatment of disease. Curr Pharm Des 2009; 15(11):
1248-1260.
[9] Williams A, Meyer D. Desferrioxamine as immunomodulatory
agent during microorganism infection. Curr Pharm Des 2009;
15(11): 1261-1268.
[10] Wong JP, Christopher ME, Viswanathan S, Dai X, Salazar
AM, Sun L-Q, Wang M. Antiviral role of Toll-like receptor-3
agonists against seasonal and avian influenza viruses. Curr
Pharm Des 2009; 15(11): 1269-1274.
Aldar S. Bourinbaiar
Immunitor USA Inc.
College Park
MD 20740
USA
E-mail: info@immunitor.com
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[Purchase
Article] [PMID: 19355957 PubMed - indexed for MEDLINE]
Clinical Experience with Therapeutic Vaccines Designed for
Patients with Hepatitis
D. Batdelger, D. Dandii, Y. Dahgwahdorj,
V. Jirathitikal and A.S. Bourinbaiar
Franciscan missionary Giovanni Di Plano Carpini traveled
in 1245 to a country named Yeke Tartar, to visit a certain
man called Genghis Khan. His journey’s report narrated
peculiar dietary habits of the locals: “they eat anything,
even lice”. Little that Carpini knew, he had actually
documented the earliest known to us record of oral vaccination
against blood-borne infections – an approach that is
still used occasionally in the present-day Mongolia for therapy
of hepatitis. Currently, efforts aimed at developing therapeutic
hepatitis vaccines have switched to more palatable path, but
we may still benefit from the insight of medieval Mongols.
This review provides an update on development of hepatitis
B and C vaccines as related to immunotherapy of hepatitis.
Immune therapy is a fast-moving field but the results so far
failed to pitch woo. Current trends in research on therapeutic
vaccine candidates and liver immunology are discussed. We
subscribe to the idea that viral hepatitis is essentially
an autoimmune disease generating immune-mediated liver damage.
Therapeutic vaccines need to be designed in such a way that
self-destructive immunity of the host is targeted not the
virus, which is not cytopathic.
[Back to top]
[Purchase
Article] [PMID: 19355958 PubMed - indexed for MEDLINE]
Design of Iodine-Lithium-α-Dextrin
Liquid Crystal with Potent Antimicrobial and Anti-Inflammatory
Properties
T.K. Davtyan, L.M. Mkhitaryan and
E.S. Gabrielyan
An ideal antimicrobial should be not toxic and possess
board spectrum antiviral, antibacterial, antifungal activity,
excluding resistance and should affect pathogen-mediated damage
of host physiology including immune, nervous and endocrine
systems. With the purpose of a combination of nonspecific
antimicrobial action of molecular and ionized iodine with
systemic immune-modulating property of the negatively charged
polysaccharides a complex drug of iodine and lithium on a
template of a α-dextrin
liquid crystal was designed. The physicochemical model of
iodine-lithium-α-dextrin
(ILαD)
is based on the human blood and the stereochemistry of moving
equilibred systems of dynamically balanced organic polymers
conformation complexed with the iodine and lithium molecules.
Here we reviewed the antibacterial, antiviral, immune-modulating
and anti-inflammatory mechanisms in vivo and in
vitro as well as pharmacokinetics, metabolism, chronic
toxicity, cumulative properties, embryo toxicity and carcinogenicity
of ILαD.
Clinical efficacy, tolerability and safety of ILαD
monotherapy have been evaluated in HIV-infected patients,
administered intravenously for a total of 12 infusions in
4 cycles. ILαD
therapy contributes to anti-HIV and anti-inflammatory effects,
resolution of dermatological and neurological pathology and
dramatically improves the quality of life reflecting on enhanced
treatment adherence. ILαD
appears to be safe and perspective for an adjuvant therapy
of bacterial and viral infections, including HIV/AIDS, hypothyroid,
autoimmune and inflammatory diseases for controlling pathogen
production from infected cells, immune response, inflammation
and metabolism.
[Back to top]
[Purchase
Article] [PMID: 19355959 PubMed - indexed for MEDLINE]
Novel Inhibitors of HIV Discovered Among Existing Classes
of Pharmaceutical Compounds Indicated for Unrelated Clinical
Indications
I.I. Kucherov, P.G. Rytik, I.A. Podol’skaya,
L.O. Mistryukova and M.O. Korjev
In vitro screening of 307 drugs with various clinical
indications (cardiotropic, neurotropic, antibacterial, etc.)
has revealed 6 compounds which displayed remarkable antiretroviral
activity. Three of these drugs had a tendency to have undesirable
side effects and were thus excluded from further consideration.
Remaining three, i.e., Xantinol Nicotinate, Tardiferon, and
Trental may become valid candidates for inclusion into antiviral
regimens such as HAART. In vitro tests have shown
that xantinol and trental display synergistic effect with
azidothymidine, inhibit the replication AZT-resistant strains
of HIV, and have no competing undesirable activities. These
compounds should be evaluated in safety studies to determine
optimal doses for patients with HIV. If these studies confirm
in vitro results these compounds may become valid
candidates as safe and affordable means to be added into the
arsenal of antiretroviral drugs.
[Back to top]
[Purchase
Article] [PMID: 19355960 PubMed - indexed for MEDLINE]
The Gut Mucosa as a Site for Induction of Regulatory T-Cells
M. Mizrahi and Y. Ilan
Regulatory T lymphocytes (Tregs) are specialized for
immune suppression and are important regulators of the immune
response in various settings. Tregs actively suppress enteroantigen-reactive
cells and contribute to the maintenance of intestinal immune
homeostasis. Distinct Treg subsets coexist in the intestinal
mucosa and mesenteric lymph nodes. Disturbances in Treg number
and function are associated with immune-mediated disorders.
Therefore, Tregs are potential targets for immunotherapies.
The gut mucosal immune system is the largest lymphoid organ
in the body. This site has continuous antigenic challenges
from food antigens, antigens of the abundant normal bacterial
flora, and pathogens. Despite this constant antigenic stimulation,
controlled inflammatory responses and suppression of inflammation
appear to be the rule. The gut immune system differentiates
the antigenic signals from the high background noise of food
and bacterial antigens. This tight regulation required to
maintain homeostasis is achieved through multiple non-immune
and immune factors.
Oral tolerance is a mechanism in which the gastrointestinal
immune system inhibits or promotes its reaction toward an
orally administered antigen. Mucosal tolerance is attractive
as an approach to the treatment of autoimmune and inflammatory
diseases; the benefits of using an oral tolerance approach
are: lack of toxicity, ease of administration over time, and
antigen-specific mechanisms of action. Multiple mechanisms
of tolerance are induced by oral antigen administration. Recent
data suggest that oral antigen administration of antigens
may promote activation of different types of regulatory T
lymphocytes, enabling treatment of immune mediated disorders.
This review summarizes the recent data on induction of regulatory
T-cells by oral antigen administration as a possible mechanism
of oral tolerance.
[Back to top]
[Purchase
Article] [PMID: 19355961 PubMed - indexed for MEDLINE]
Attenuated D2 16681-PDK53 Vaccine: Defining Humoral and Cell
Mediated Immunity
J. Rabablert and S. Yoksan
Dengue viruses cause 50-100 million cases of acute febrile
disease every year, including more than 500000 reported cases
of the severe forms of the disease-dengue hemorrhagic fever
(DHF) and dengue shock syndrome (DSS). Attempts to create
conventional vaccines have been hampered by the lack of suitable
experimental models, the need to provide protection against
all four serotypes simultaneously and the possible involvement
of virus-specific immune responses in severe disease. Live
attenuated D2 16681-PDK53 vaccine was first developed from
Mahidol University, Thailand. This vaccine induced both humoral
and cell-mediated immunity and lack of reactogeneticity in
humans. Infectious cDNA clones of the virulent D2 16681 virus
and its attenuated D2 16681-PDK53 were constructed. The attenuated
virus elicited neutralizing antibodies in mice and monkeys
and developed viremia in monkeys. At molecular level, patterns
of cytokines which are immunological mediators released from
human mononuclear cells obtained from dengue naïve and
immune donors infected with this attenuated virus compared
with virulent virus were studied. In dengue naïve PBMC,
the virulent and attenuated clones induced alternation in
expression of 25 and 24 versus 13 and 18 genes out of 268
genes on day 1 and 3. In dengue immune PBMC, the virulent
and attenuated clones induced alternation in expression of
33 and 38 versus 25 and 29 genes on days 1 and 3. Up-regulation
of IL-1β,
IL-6, IL-8, IL-10, IFN-α,
IFNγR,
MIP-1α,
MIP-1β,
MIP-2α,
VEGF and down-regulation of IL-4, IL-4R, IL-RII, MIF, RANTES,
IGF-1, GM-CSF-2 were shown. This review pointed out the infectious
clones of the attenuated D2 16681-PDK53 was safe and induced
both neutralizing antibodies in vivo and cytokine
gene expression in vitro at molecular level. Furthermore,
the phenotypic markers of ideal dengue vaccine could be included
the alteration of cytokine gene expression and cytokine production
in human mononuclear cells.
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[Purchase
Article] [PMID: 19355962 PubMed - indexed for MEDLINE]
Inhibition of Transcription Factors by Plant-Derived Compounds
and their Implications in Inflammation and Cancer
J.L. Ríos, M.C. Recio, J.M. Escandell
and I. Andújar
Inflammation is a general term used to describe various
pathological processes with diverse causes that can include
infection, trauma, or an autoimmune response. Due to its many
causes, the inflammatory response involves multiple and varied
mediators, including vasoactive amines, free radicals, and
both lipidic and peptidic mediators.
Medicinal plants and the compounds derived from them are a
good source of new and specific inhibitors of the inflammatory
process. The past decade has witnessed many important discoveries
in this field, with new findings challenging the more traditional
views of pharmacologists. Various studies, for example, have
demonstrated the positive effects of plant-derived phenolics,
which act as anti-oxidants, free radical scavengers, and inhibitors
of nitric-oxide synthase, cyclooxy-genase, and lipoxygenase.
The anti-inflammatory activity of chalcones has been correlated
with the induction of heme oxygenase-1 while phlorotannins
have been found to inhibit matrix metalloproteinase, which
is implicated in arthritis, chronic inflammation, and wrinkle
formation. Sesquiterpene lactones have been studied as inhibitors
of NF-κB
activity and the relationship between their chemical structure
and pharmacological activity has been clearly established.
Recently, cucurbitacins have been described as inhibitors
of JAK –STAT and NF-AT functions related to inflammation;
they were also found to induce apoptosis of cells involved
in the inflammatory response. This review focuses mainly on
the effects of natural products on transcription factors,
which are the most promising targets for designing new active
drugs against inflammation and cancer.
[Back to top]
[Purchase
Article] [PMID: 19355963 PubMed - indexed for MEDLINE]
Synthetic and Natural Immunomodulators Acting as Interferon
Inducers
D.S. Silin, O.V. Lyubomska, F.I. Ershov,
V.M. Frolov and G.A. Kutsyna
Interferons are first immunomodulatory molecules that
have been shown to display a wide range of applications due
to their antiviral, antibacterial, antitumor, and inflammatory
activities. Natural and recombinant interferons are among
most common biologic therapeutics worldwide. Interferon inducers,
however, are less known and have been mostly developed and
used in former socialist countries. Despite the fact that
they are virtually unknown to the Western world, they represent
a substantial market share of modern pharmacopoeia in former
socialist republics. This review provides a brief description
of most popular interferon inducers including Amyxin, Amizon,
Anandin, Arbidol, Blasten, Cycloferon, Galavit, Groprinosine,
Hepon, Immunoxel, Dzherelo, Kagocel, Larifan, Ligfol, Likopid,
Mebavin, MIGI-KLP, V-5 Immunitor, SCV-07, Milife, Neovir,
Poludan, Ragocin, Ridostin, Thymogen and Savratz, some of
which were in use for several decades for the same clinical
indications as for interferons. The variety and choice offered
by the pharmaceutical industry behind the former “iron
curtain” certainly deserves the appreciation, familiarity
and application prospects for medical and research investigators
worldwide.
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[Purchase
Article] [PMID: 19355964 PubMed - indexed for MEDLINE]
The Common Mycobacterial Antigens and their Importance in
the Treatment of Disease
J. Stanford, C. Stanford, G. Stansby, O.
Bottasso, G. Bahr and J. Grange
The mycobacteria are one of a number of genera making
up the aerobic Actinomycetales. Their antigens demonstrable
by immuno-precipitation methods can be divided into four groups.
The group i antigens, common to all mycobacterial species,
cross-react with their counterparts in animal cells, largely
derived from mitochondria. Notable amongst these antigens
are the heat-shock, or stress, proteins and possibly bacterial
sugars.
Tests of cell-mediated immunity show that people can be separated
by their responsiveness in skin-test, or lymphocyte proliferation
techniques, into four categories of responders. Category 1
individuals respond to all mycobacterial reagents through
recognition of the group i antigens.
Many chronic diseases are associated with a lack of cell-mediated
responsiveness to the group i antigens, and have a raised
antibody titre to them. This reflects a predominance of T
helper 2 activity and reduced T helper 1 responsiveness as
part of the pathogenesis of their diseases, which include
chronic bacterial, viral and parasitic infections, allergies,
auto-immunities and neoplasms.
Packaged together, the group i antigens and the cell-wall
adjuvants of selected aerobic Actinomycetales make potent
immuno-modulatory reagents. An example is heat-killed Mycobacterium
vaccae, useful in both prevention and treatment of disease.
Treatment with such reagents results in alleviation of disease,
restoration of cellular responsiveness to the common mycobacterial
antigens and a decrease in antibody titres to them.
This new approach to treatment for such a wide range of diseases
has few disadvantageous side effects and can accompany other
non-immunosuppressive therapies.
[Back to top]
[Purchase
Article] [PMID: 19355965 PubMed - indexed for MEDLINE]
Desferrioxamine as Immunomodulatory Agent During Microorganism
Infection
A. Williams and D. Meyer
Southern Africa is burdened with Human Immunodeficiency
Virus (HIV) and Mycobacterium tuberculosis (M.tuberculosis)
infections as well as conditions of iron (Fe) overload. Highly
Active Antiretroviral Therapy (HAART) is used to treat HIV-infection,
many drugs exist for the treatment of tuberculosis (new solutions
are also being sought because of the existence of multi drug
resistant strains of M.tuberculosis) and Fe chelators
are commonly used to treat Fe overload. Chelators have also
been shown to inhibit the multiplication of numerous microorganisms
and hence there are publications suggesting a role for chelators
like desferrioxamine (DFO) in the dual treatment of microorganism
infection and excess iron. Excess iron fuels pathogen survival
which in turn lowers host cell functionality (manifested as
altered proliferation, cytokine secretion, etc); withholding
iron (via a chelator) reverses the process, even
more so when the cells are chelated for longer periods of
time. Chelation with DFO is reviewed here by commenting on
its immunomodulatory effect.
[Back to top]
[Purchase
Article] [PMID: 19355966 PubMed - indexed for MEDLINE]
Antiviral Role of Toll-Like Receptor-3 Agonists Against Seasonal
and Avian Influenza Viruses
J.P. Wong, M.E. Christopher, S. Viswanathan,
X. Dai, A.M. Salazar, L. Q. Sun and M. Wang
The divergence and antigenic shifts in influenza viruses
represent significant challenges for the development of effective
vaccines and antiviral drugs against influenza viruses. In
view of current challenges and/or deficiencies in the influenza
pandemic influenza preparedness, novel antiviral strategies
which are robust and can respond to constant viral mutations,
are particularly needed to combat future pandemic threats.
Toll-like receptor-3 (TLR-3) is an integral part of the host’s
innate immune system and serves as an important signaling
pathway for the recognition of dsRNA for the triggering of
antiviral and inflammatory responses to combat viral infections.
This review examines dsRNA including Poly ICLC and liposome-encapsulated
Poly ICLC (LE Poly ICLC) as TLR-3 agonists for their antiviral
activity against seasonal and highly pathogenic avian influenza
(HPAI) viruses. Furthermore, their roles in attenuating the
antiviral and inflammatory cytokines in the host will also
be explored. Preclinical studies in experimental animals suggest
Poly ICLC and liposome-encapsulated Poly ICLC are safe and
offer broad-spectrum protection against both seasonal and
HPAI viruses, as well as other respiratory viruses including
respiratory syncytial virus and SARS. Preliminary results
from recent studies suggest these drugs up-regulate the production
of interferons (-α,
-β,
and –γ),
and tumor necrosis factor (TNF-α)
but downregulate some proinflammatory cytokines including
IL-2 and IL-4.
Taken together, these results suggest these TLR-3 agonists
have a promising role to play as safe, effective and broad-spectrum
anti-influenza drugs that could complement other antiviral
drugs to combat seasonal, zoonotic and pandemic influenza
viruses. The clinical safety of these drugs and their efficacy
in pre-clinical studies may provide sufficient justification
for regulatory agencies to consider their fast track development
for use in future outbreaks of pandemic influenza or of other
emerging respiratory pathogens.
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