| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 20, 2010
Contents
Current Advances in Anti-Influenza Therapy Pp. 2101-2140
R. Saladino, M. Barontini, M. Crucianelli, L. Nencioni,
R. Sgarbanti and A.T. Palamara
[Abstract] [Purchase
Article] [PMID:
20423307 PubMed - indexed for MEDLINE]
Impact on DNA Methylation in Cancer Prevention
and Therapy by Bioactive Dietary Components Pp. 2141-2151
Y. Li and T.O. Tollefsbol
[Abstract] [Purchase
Article] [PMID:
20423306 PubMed - indexed for MEDLINE]
Editor’s Choice
Oxidative Stress and NAD+ in Ischemic Brain Injury:
Current Advances and Future Perspectives Pp. 2152-2158
W. Ying and Z.-G. Xiong
[Abstract]
[Purchase
Article] [PMID:
20423305 PubMed - indexed for MEDLINE]
Neurogenesis: Role for microRNAs and Mesenchymal Stem Cells
in Pathological States Pp. 2159-2167
P.K. Lim, S.A. Patel, L.A. Gregory and P. Rameshwar
[Abstract]
[Purchase
Article] [PMID:
20423304 PubMed - indexed for MEDLINE]
Regulatory Effects of Peptides from the Pro and Catalytic
Domains of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9)
on Low-Density Lipoprotein Receptor (LDL-R) Pp. 2168-2182
H. Palmer-Smith and A. Basak
[Abstract]
[Supplementary
Material] [Purchase
Article] [PMID:
20423303 PubMed - indexed for MEDLINE]
Structure-Function Relationships and Clinical Applications
of L-Asparaginases Pp. 2183-2195
N.E. Labrou, A.C. Papageorgiou and V.I. Avramis
[Abstract]
[Purchase
Article] [PMID:
20423302 PubMed - indexed for MEDLINE]
Anti-Diabetic Effect of Trigonelline and Nicotinic Acid, on
KK-Ay Mice Pp. 2196-2202
O. Yoshinari and K. Igarashi
[Abstract]
[Purchase
Article] [PMID:
20423301 PubMed - indexed for MEDLINE]
Assessing Structure, Function and Druggability of
Major Inhibitory Neurotransmitter γ-Aminobutyrate Symporter
Subtypes Pp. 2203-2213
J. Kardos, A. Palló, Á. Bencsura and
Á. Simon
[Abstract]
[Purchase
Article] [PMID:
20423300 PubMed - indexed for MEDLINE]
Abstracts
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[Purchase
Article] [PMID:
20423307 PubMed - indexed for MEDLINE]
Current Advances in Anti-Influenza Therapy
R. Saladino, M. Barontini, M. Crucianelli, L. Nencioni,
R. Sgarbanti and A.T. Palamara
Every year, influenza epidemics cause numerous deaths and
millions of hospitalizations, but the most frightening effects
are seen when new strains of the virus emerge from different
species (e.g. the swine-origin influenza A/H1N1 virus), causing
world-wide outbreaks of infection. Several antiviral compounds
have been developed against influenza virus to interfere with
specific events in the replication cycle. Among them, the
inhibitors of viral uncoating (amantadine), nucleoside inhibitors
(ribavirin), viral transcription and neuraminidase inhibitors
(zanamivir and oseltamivir) are reported as examples of traditional
virus-based antiviral strategies. However, for most of them
the efficacy is often limited by toxicity and the almost inevitable
selection of drug-resistant viral mutants. Thus, the discovery
of novel anti-influenza drugs that target general cell signaling
pathways essential for viral replication, irrespective to
the specific origin of the virus, would decrease the emergence
of drug resistance and increase the effectiveness towards
different strains of influenza virus. In this context, virus-activated
intracellular cascades, finely regulated by small changes
in the intracellular redox state, can contribute to inhibit
influenza virus replication and pathogenesis of virus-induced
disease. This novel therapeutic approach involves advanced
cell-based antiviral strategies. In this review current advances
in the anti-influenza therapy for both traditional virus-based
antiviral strategies as well as for alternative cell-based
antiviral strategies are described focusing on the last 10
years. Anti-influenza compounds are classified on the basis
of their chemical structure with a special attention to describe
their synthetic pathways and the corresponding structure activity
relationships.
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[Purchase Article] [PMID:
20423306 PubMed - indexed for MEDLINE]
Impact on DNA Methylation in Cancer Prevention and Therapy
by Bioactive Dietary Components
Y. Li and T.O. Tollefsbol
It is well established that aberrant gene regulation by epigenetic
mechanisms can develop as a result of pathological processes
such as cancer. Methylation of CpG islands is an important
component of the epigenetic code and a number of genes become
abnormally methylated during tumorigenesis. Some bioactive
food components have been shown to have cancer inhibition
activities by reducing DNA hypermethylation of key cancer-causing
genes through their DNA methyltransferase (DNMT) inhibition
properties. The dietary polyphenols, (-)-epigallocatechin-3-gallate
(EGCG) from green tea, genistein from soybean and possibly
isothiocyanates from plant foods, are some examples of these
bioactive food components modulated by epigenetic factors.
The activity of cancer inhibition generated from dietary polyphenols
is associated with gene reactivation through demethylation
in the promoters of methylation-silenced genes such as p16INK4a
and retinoic acid receptor β. The effects of dietary
polyphenols such as EGCG on DNMTs appear to have their direct
inhibition by interaction with the catalytic site of the DNMT1
molecule, and may also influence methylation status indirectly
through metabolic effects associated with energy metabolism.
Therefore, reversal of hypermethylation-induced inactivation
of key tumor suppression genes by dietary DNMT inhibitors
could be an effective approach to cancer prevention and therapy.
In this analysis, we focus on advances in understanding the
effects of dietary polyphenols on DNA methylation modulation
during the process of cancer development, which will offer
exciting new opportunities to explore the role of diet in
influencing the biology of cancer and to understand the susceptibility
of the human epigenome to dietary effects.
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Oxidative Stress and NAD+ in Ischemic Brain Injury:
Current Advances and Future Perspectives
W. Ying and Z.-G. Xiong
Numerous studies have indicated oxidative stress as a key
pathological factor in ischemic brain injury. One of the key
links between oxidative stress and cell death is excessive
activation of poly(ADP-ribose) polymerase-1 (PARP-1), which
plays an important role in the ischemic brain damage in male
animals. Multiple studies have also suggested that NAD+
depletion mediates PARP-1 cytotoxicity, and NAD+
administration can decrease ischemic brain injury.
A number of recent studies have provided novel information
regarding the mechanisms underlying the roles of oxidative
stress and NAD+-dependent enzymes in ischemic brain injury.
Of particular interest, there have been exciting progresses
regarding the mechanisms underlying the roles of NADPH oxidase
and PARP-1 in cerebral ischemia. For examples, it has been
suggested that androgen signaling and binding of PARP-1 onto
estrogen receptors could account for the intriguing findings
that PARP-1 plays remarkably differential roles in the ischemic
brain damage of male and female animals; and some studies
have suggested casein kinase 2, copper-zinc superoxide dismutase,
and estrogen signaling can modulate the expression and activity
of NADPH oxidase.
This review summarizes these important current advances, and
proposes future perspectives for the studies on the roles
of oxidative stress and NAD+ in cerebral ischemia. It is increasingly
likely that future studies on NAD- and NADP-dependent enzymes,
such as NADPH oxidase, PARP-1, and sirtuins, would expose
novel mechanisms underlying the roles of oxidative stress
in cerebral ischemia, and suggest new therapeutic strategies
for treating the debilitating disease.
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[Purchase
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20423304 PubMed - indexed for MEDLINE]
Neurogenesis: Role for microRNAs and Mesenchymal Stem
Cells in Pathological States
P.K. Lim, S.A. Patel, L.A. Gregory and P. Rameshwar
Implantation of adult human mesenchymal stem cells (MSCs)
to treat neural disorders shows promise. Depending on their
microenvironment, MSCs could potentially be used for the repair
and/or replacement of neurons in traumatic brain injury or
the treatment of Parkinson’s disease. This cross-disciplinary
review incorporates aspects of neuroscience, stem cell biology,
cancer biology and immunology to discuss interactions between
inflammatory mediators and MSCs. We first discuss the role
of microRNAs (miRNAs) in neurological development. Secondly,
we discuss the ability of MSCs to transdifferentiate into
functional neurons, which are regulated by miRNAs, and the
implications of these cells for the therapy of neuropathological
states. The administration of effective and safe MSC therapy
must acknowledge immune mediators that may predispose the
early differentiating MSCs to oncogenic insults. Thus, we
discuss a key gene, RE-1 silencing transcription factor (REST),
based on its dual role in neurogenesis and cancer development.
Immune mediators could be central to MSC responses within
a region of tissue injury and are also discussed in detail.
Exploring the predisposition of MSCs to oncogenesis is critical
for translational science since the implementation of safeguarding
measures prior to therapy can lead to the successful delivery
of stem cells to patients. The method by which MSCs could
be applied for future therapies might require trans-disciplinary
approaches for personalized treatments.
[Back to top] [Purchase
Article] [PMID:
20423303 PubMed - indexed for MEDLINE]
Regulatory Effects of Peptides from the Pro and Catalytic
Domains of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9)
on Low-Density Lipoprotein Receptor (LDL-R)
H. Palmer-Smith and A. Basak
[Supplementary
Material]
Background: Proprotein Convertase Subtilisin/Kexin
9 (PCSK9) is a Proteinase K subtype of mammalian subtilases
collectively called PCSKs. PCSK9 upregulates plasma-cholesterol
level by degrading low-density lipoprotein receptor (LDL-R).
As a result, PCSK9 is a major target for intervention of hypercholesterolemia
and in this regard PCSK9-inhibitors may find useful therapeutic
and biochemical applications.
Objective: Our objective is to develop short peptide
based PCSK9 inhibitors from its own pro and/or catalytic domains.
Results: Using human (h) hepatic HepG2 and Huh7 cells
we showed that the acidic N-terminal hPCSK9Na31-60,
31-40 and the mid-basic hPCSK9091-120
peptides derived from hPCSK9-prodomain significantly enhanced
LDL-R level without altering PCSK9 content. Moreover, the
physiologically relevant phoshpho-SerNa47
and sulpho-YNa38 containing
hPCSK9Na31-60 peptides diminished
LDL-R level suggesting that such posttranslational modifications
in the prodomain lead to gain of PCSK9-functional activity.
These modifications are thus expected to lead to even higher
level of plasma cholesterol. As expected, addition of purified
recombinant-PCSK9 to the culture medium decreased LDL-R level
which can be restored back by exogenous addition of hPCSK9Na31-40,
31-60 or Na91-120
peptides. Using a series of truncated peptides, we identified
the most potent LDL-R promoting activity to reside within
the prodomain sequence hPCSK9Na31-37.
Two catalytic domain peptides hPCSK9Na181-200
and hPCSK9Na368-390, containing
proposed LDL-R interacting sites have been shown to diminish
LDL-R level.
Conclusion: Our study concludes that specific peptides
from pro- and catalytic domains of hPCSK9 can regulate LDL-R
in cell based assay and may be useful for development of novel
therapeutics for cholesterol regulation.
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[Purchase
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20423302 PubMed - indexed for MEDLINE]
Structure-Function Relationships and Clinical Applications
of L-Asparaginases
N.E. Labrou, A.C. Papageorgiou and
V.I. Avramis
L-Asparaginase (L-ASNase, EC 3.5.1.1) catalyzes the hydrolysis
of the non-essential amino acid L-Asn to L-Asp and ammonia
and is widely used for the treatment of haematopoetic diseases
such as acute lymphoblastic leukaemia (ALL) and lymphomas.
Therapeutic forms of L-ASNase come from different biological
sources (primarily E. coli and Erwinia chrysanthemi).
It is well established that the various preparations have
different biochemical pharmacology properties, and different
tendency to induce side-effects. This is due to different
structural, physicochemical and kinetic properties of L-ASNases
from the various biological sources. Understanding these properties
of various L-ASNases would allow a better decipherment of
their catalytic and therapeutic features, thus enabling more
accurate predictions of the behaviour of these enzymes under
a variety of therapeutic conditions. In addition, detailed
understanding of the catalytic mechanism of L-ASNases might
permit the design of new forms of L-ASNases with optimal biochemical
properties for clinical applications. In this paper we review
the available biochemical and pharmacokinetic information
of the therapeutic forms of bacterial L-ASNases, and focus
on a detailed description of structure, function and clinical
applications of these enzymes.
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[Purchase
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Anti-Diabetic Effect of Trigonelline and Nicotinic
Acid, on KK-Ay Mice
O. Yoshinari and K. Igarashi
Trigonelline (TRG) and nicotinic acid (NA), in which
the former but not the latter improved the blood glucose level
in the oral glucose tolerance test (OGTT) in Goto-Kakizaki
(GK) rats were tested for anti-diabetic effects in mellitus
models of KK-Ay
obese mice that had type 2 diabetes.
Blood glucose level in OGTT carried out on day 22-23 was lowered
after feeding in mice fed TRG and NA than that of the control
mice not fed these compounds, indicating that both TRG and
NA have sufficient activity to improve glucose tolerance in
diabetes with obesity. The serum insulin levels at fasting
showed significantly lower levels in mice fed TRG, and a lower
tendency in mice fed NA, compared with the control mice. The
triglyceride (TG) levels in the liver and adipose tissue in
mice fed TRG and NA showed lower values or a lower tendency
than those of the control mice, indicating that TRG and NA
were also effective to improve the changes in lipid levels
accompanied with diabetes. Higher values or a higher tendency
of the glucokinase (GLK) / glucose-6-phosphatase (G6Pase)
ratio in the liver and lower levels of the serum tumor necrosis
factor (TNF) -α in the TRG- and NA-fed mice, compared
to the control mice, suggested that the regulation of GLK
and G6Pase, and TNF-a production by TRG and NA are closely
related in suppressing the progression of diabetes in the
KK-Ay mice.
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[Purchase
Article] [PMID:
20423300 PubMed - indexed for MEDLINE]
Assessing Structure, Function and Druggability of
Major Inhibitory Neurotransmitter γ-Aminobutyrate Symporter
Subtypes
J. Kardos, A. Palló, Á. Bencsura and
Á. Simon
Ambient level of γ-aminobutyric acid (GABA), the major
inhibitory neurotransmitter of the brain is mediated by neuronal
and glial GABA transporters (GATs), members of the sodium
and chloride ion-dependent solute carrier family. The neuronal
GABA transporter subtype (GAT-1) has already been proven to
be the target for the antiepileptic drug Tiagabine. However,
druggability of glial GAT-2 and GAT-3 is yet to be established.
Recent advances in structure elucidation of a bacterial orthologue
leucine transporter in complex with different substrates substantiate
homology modeling of human GATs (hGATs). These modeling studies
can provide mechanistic clues for structure-based prediction
of the potential of medicinal chemistry campaigns. A recently
identified characteristic structural feature of the occluded
conformation of hGATs is that similar extra- and intracellular
gates are formed by middle-broken transmembrane helices TM1
and TM6. Binding crevice formed by unwound segments of broken
helices facilitates symport of GABA with Na+
ion via fitting of GABA to TM1-bound Na+(1)
closely inside. Favored accommodation of substrate inhibitors
with high docking score predicts efficient inhibition of the
neuronal hGAT-1 if the TM1-TM8 binding prerequisite for GABA
was used. Docking, molecular dynamics and transport data indicate,
that amino acids participating in substrate binding of the
neuronal hGAT-1 and the glial hGAT-2 and hGAT-3 subtypes are
different. By contrast, substrate binding crevices of hGAT-2
and hGAT-3 cannot be distinguished, avoiding sensible prediction
of efficient selective substrate inhibitors. Glial subtypes
might be specifically distinguished by interfering Zn2+
binding in the second extracellular loop of hGAT-3. Formation
of the unique ring-like Na+-GABA
complex in the occluded binding crevices anticipates family
member symporters exploring chemiosmotic energy via
reversible chemical coupling of Na+
ion.
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