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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 14, 2006
Contents
Design of Peptide-Based Vaccines for Cancer Pp.
1591-1607
G.A. Pietersz, D.S. Pouniotis and V. Apostolopoulos
[Abstract]
Ceramide in Apoptotic Signaling and Anticancer Therapy Pp.
1609-1616
C.F. Lin, C.L. Chen and Y.S. Lin
[Abstract]
Macromolecular Ensembles of Internal and External Fibrinolysis:
the Resources for Enhancement of Thrombolysis Efficacy Pp.
1617-1625
Alexander V. Maksimenko and Elena G. Tischenko
[Abstract]
Gene-Gene and Gene-Environment Interplay Represent Specific
Susceptibility for Different Types of Ischaemic Stroke and
Leukoaraiosis Pp. 1627-1634
Zoltán Szolnoki and Béla Melegh
[Abstract]
Pharmacological Treatment of Atrial Fibrillation:
Mechanisms of Action and Efficacy of Class III Drugs
Pp. 1635-1653
Federico Lombardi and Paolo Terranova
[Abstract]
Endothelin-1: The Yin and Yang on Vascular Function
Pp. 1655-1665
Flora Linda Marasciulo, Monica Montagnani and Maria Assunta
Potenza
[Abstract]
Homology Modeling of G-Protein-Coupled Receptors and
Implications in Drug Design Pp. 1667-1691
Akshay Patny, Prashant V. Desai and Mitchell A. Avery
[Abstract]
Insights into Mechanism of NMD: Digging from the NMD-Related
Protein Complexes Pp. 1693-1705
Zhen-Ya Li, Xi-Song Ke, De-Pei Liu and Chih-Chuan Liang
[Abstract]
A Review of Current Knowledge of the Complement System
and the Therapeutic Opportunities in Inflammatory Arthritis
Pp. 1707-1717
M. Mizuno
[Abstract]
Abstracts
[Back to top]
Design of Peptide-Based Vaccines for Cancer
G.A. Pietersz, D.S. Pouniotis and V. Apostolopoulos
The immune system responds efficiently to bacteria,
viruses and other agents however, the immune response to cancers
is not as effective. In most cases other than specific genetic
rearrangements leading to non-self proteins such as in leukemia
and idiotypes in lymphoma, tumor associated proteins are self
proteins and are not recognized by the immune system to prevent
malignancy. In most cancers, patients develop antibodies and/or
CTL-precursors to tumor associated antigens but are not effective
in generating a therapeutic immune response. Adjuvants have
been used with either whole tumors, subunits or peptides with
the aim of increasing their immunity. Whole tumor antigens
have certain advantages associated with it, such as ready
availability as recombinant proteins, potential epitopes that
can be presented by a number of MHC class I/II alleles and
antibody development. The methods of identification of CD8
and CD4 epitopes either by use of epitope prediction algorithms
or use of transgenic mice has made the use of defined synthetic
peptides more attractive. The possibility to synthesize long
peptides and introduce multiple epitopes (CD4 or CD8) from
single or multiple antigens makes peptide a viable alternative
to whole proteins. As an alternative to totally synthetic
peptide constructs or polymers, polytopes have been generated
by genetic engineering methods. In addition, to deliver immunogens
to and to activate DC, receptor-mediated delivery of peptides
using antibodies, cytokines and carbohydrates have been used.
This review will encompass the various strategies, preclinical
and clinical applications in designing peptide-based vaccines
for cancer.
[Back to top]
Ceramide in Apoptotic Signaling and Anticancer Therapy
C.F. Lin, C.L. Chen and Y.S. Lin
Ceramide, a product of sphingolipid metabolism,
is generated in response to various stress stimuli, such as
tumor necrosis factor-α,
CD95/Fas, chemotherapeutic agents, and irradiation. Ceramide
may modulate the biochemical and cellular processes that lead
to apoptosis. However, the mechanisms by which ceramide regulates
apoptotic events are not fully defined. It is believed that
the biological effect of ceramide depends on its concentration,
the activation or differentiation status of the cell, and
the time frame of action. Here, we discuss the metabolism
and cell apoptotic signaling of ceramide. The involvement
of protein kinases (i.e. PI3K/Akt and GSK-3β)
and protein phosphatases (i.e. PP1 and PP2A), Bcl-2 family
proteins, mitochondrial damage, and caspase cascade activation
are demonstrated. Further, ceramide and its derivatives have
recently been incorporated into strategies for anticancer
therapies. An understanding of the apoptotic signaling pathways
mediated by ceramide may shed light on its potential for therapeutic
intervention.
[Back to top]
Macromolecular Ensembles of Internal and
External Fibrinolysis: the Resources for Enhancement of Thrombolysis
Efficacy
Alexander V. Maksimenko and Elena G. Tischenko
The results of the search for new plasminogen activators
for thrombolytic therapy have been reviewed with analysis
of slowdown in this process. The reserves of increasing the
effectiveness of thrombolysis are considered and the mechanisms
underlying the interactions between plasminogen and its activators
with fibrin are described. The domain composition of the fibrinolytic
agents and the functional role of their structural elements
in fibrinolytic interactions are discussed. The action of
fibrin-specific and fibrin-nonspecific plasminogen activators
in fibrinolysis has been evaluated. The necessity of the investigation
of the regularities of internal and external fibrinolysis
has been substantiated. The internal fibrinolysis became the
resource for enhancement of thrombolysis efficacy. The approaches
to the use of internal fibrinolysis to increase the effectiveness
of enzyme therapy (monotherapy with plasminogen or new-made
plasminogen activator as well as polytherapy with combination
of different plasminogen activators /thrombolysis trigger
plus third-generaton plasminogen activator of prolonged action/)
have been outlined and the relationship between this research
and the current tendencies in the improvement of clinical
thrombolysis (dose reduction, adjacent therapy, etc.) has
been discussed.
[Back to top]
Gene-Gene and Gene-Environment Interplay Represent
Specific Susceptibility for Different Types of Ischaemic Stroke
and Leukoaraiosis
Zoltán Szolnoki and Béla Melegh
Stroke is a very frequent entity. It is the third leading
cause of death and the leading cause of adult disability in
the developed world. At a population level, the common sporadic
form of ischaemic stroke is underpinned by both environmental
and genetic risk factors. Typically, in clinical practice,
environmental risk factors such as hypertension, diabetes
mellitus, smoking, alcohol consumption, and other factors,
are usually considered to be more important than genetic factors.
However, it is the interplay of both environmental and common
genetic factors [such as the Leiden V, methylenetetrahydrofolate
reductase C677T, apolipopotein E 4, endothelial nitric oxide
synthase G894T, angiotensin-converting enzyme I/D and angiotensin
II type 1 receptor A1166C mutations and polymorphisms] that
leads to the development of ischaemic stroke. Indeed, a complex
network of interactions between genetic factors and clinical
risk factors can be supposed. This review evaluates the possible
roles of gene-gene and gene-environment interactions concerning
the above genetic factors in the evolution of ischaemic stroke
and leukoaraiosis.
A knowledge of the specific genetic patterns which are associated
with a significant risk of ischaemic stroke or leukoaraiosis
may also draw attention to a large population at an increased
risk of circulatory disorders. This may facilitate the choice
of more effective and specific prevention on the basis of
the genotype.
[Back to top]
Pharmacological Treatment of Atrial Fibrillation:
Mechanisms of Action and Efficacy of Class III Drugs
Federico Lombardi and Paolo Terranova
Atrial fibrillation represents a major clinical, social
and economical matter, and its importance is expected to increase
even more in the near future. The progressive ageing of population
is associated with an inevitable rising in incidence and prevalence
of this rhythm disorder, which limits functional capability,
favours occurrence of cerebrovascular events and increases
people’s request for emergency room visits and hospital
recovery.
In spite of the increasing successes of the interventional
non-pharmacological therapies, drug treatment of patients
with atrial fibrillation in relation to conversion to sinus
rhythm and prevention of recurrences, maintains a critical
role. Several antiarrhythmic drugs are nowadays available,
but their efficacy is limited by the high rate of arrhythmias
recurrences and by side effects during acute and chronic treatment.
Drugs interfering with potassium channels (Class III drugs)
have been proposed and used in patients with atrial fibrillation.
Aim of this review is to discuss the most recent data on the
efficacy and feasibility of class III drugs in atrial fibrillation.
Experimental and clinical data on dronedarone, ibutilide,
dofetilide, azimilide, ersentilide and ambasilide will be
hereby discussed.
[Back to top]
Endothelin-1: The Yin and Yang on Vascular Function
Flora Linda Marasciulo, Monica Montagnani and Maria Assunta
Potenza
Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial
cells, which acts as the natural counterpart of the vasodilator
nitric oxide (NO). ET-1 contributes to vascular tone and regulates
cell proliferation through activation of ETA and ETB receptors.
Physical factors such as shear stress, or stimuli including
thrombin, epinephrine, angiotensin II, growth factors, cytokines
and free radicals enhance secretion of ET-1. By contrast,
mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic
peptide, and prostacyclin reduce the release of endogenous
ET-1. Thus, under normal conditions, the effects of the ET-1
are carefully regulated through inhibition or stimulation
of ET-1 release from endothelium.
Endothelial dysfunction is one of the earliest landmarks of
vascular abnormalities. Altered function of endothelium may
result from absolute decrease in bioavailability of NO as
well as from relative augment in ET-1 synthesis, release or
activity. Imbalance in the production of vasodilator and vasoconstrictor
agents may contribute to the onset of hemodynamic disorders.
Since dysregulation of the endothelin system is important
in the pathogenesis of several cardiovascular diseases, the
ETA and ETB receptors are attractive therapeutic targets for
disorders associated with elevated ET-1 levels. ET receptor
antagonists may be regarded as disease-modifying agents thanks
to their ability to preserve endothelial integrity when the
endothelin system is overactive.
This review summarizes the current knowledge on the role of
ET-1 in experimental hypertension and describes recent findings
on the involvement of MAPK signalling pathways in ET-1 release
in hypertension associated with insulin resistance.
Moreover, therapeutic applications of ET-1 receptor blockers
are also discussed.
[Back to top]
Homology Modeling of G-Protein-Coupled Receptors and
Implications in Drug Design
Akshay Patny, Prashant V. Desai and Mitchell A. Avery
G-protein-coupled receptors (GPCRs) are considered therapeutically
important due to their involvement in a variety of processes
governing several cellular functions, and their tractability
as drug targets. A large percentage of drugs on the market,
and in development stages, target the super family of the
GPCRs. The enormous interest in GPCR drug design is, however,
limited by the scarcity of structural information. The only
GPCR for which a three dimensional (3D) structure is reported
is bovine rhodopsin and it belongs to class A of the GPCR
family. As a result, there has been considerable interest
in alternative techniques, for example, homology modeling
of GPCRs, in order to derive useful three dimensional models
of other proteins for use in structure-based drug design.
However, homology modeling of GPCRs is not straightforward,
and encounters several problems, owing to the availability
of a single structural template, as well as the low degree
of sequence homology between the template and target sequences.
There are several key issues which need to be considered during
every stage of GPCR homology modeling, in order to derive
reasonable 3D models. Homology modeling of GPCRs has been
utilized increasingly in the past few years and has been successful,
not only in furthering the understanding of ligand-protein
interactions, but also in the identification of new and potent
ligands. Thus, with the lessons learned from past experiences
and new developments, homology modeling in case of GPCRs can
be harnessed for developing more reliable three dimensional
models. This, in turn, will provide better tools to use in
structure-based drug design leading to the identification
of novel and potent GPCR ligands for several therapeutic indications.
[Back to top]
Insights into Mechanism of NMD: Digging from the NMD-Related
Protein Complexes
Zhen-Ya Li, Xi-Song Ke, De-Pei Liu and Chih-Chuan Liang
Nonsense-mediated RNA decay (NMD), an mRNA quality control
mechanism, triggers degradation of mRNAs that contain premature
termination codon (PTC) within their coding regions. NMD is
a relatively conservative process that involves many trans-acting
factors. The key domains for their function in NMD are conserved
in evolution. These trans-acting factors are classified
as different groups by their function in NMD. In addition,
the mRNP formation is dynamic in NMD process because of sequential
recruitment and interaction of these factors. To gain an insight
into the mechanism of NMD, we dissect the mechanism of NMD
based on the information on the structure, the regulation
and interaction of these factors.
[Back to top]
A Review of Current Knowledge of the Complement
System and the Therapeutic Opportunities in Inflammatory Arthritis
M. Mizuno
The complement activation system, a key component of
the innate immune system, protects the host from microorganisms
such as bacteria, and other foreign threats including abnormal
cells. However, it is also double-edged in that it can have
negative effects in the host; excessive complement activation
damages the host and can even kill in anaphylactic shock and
septic shock. Regulation of the complement system is a useful
strategy to control inflammatory diseases, including inflammatory
arthritis. Rheumatoid arthritis is a common inflammatory disease
worldwide. Many medicines are developed to control inflammation,
including recently developed biological response modifiers
such as anti-TNF and IL-6 agents. Nevertheless, in some patients
disease remains difficult to control because of complications,
side effects and tolerance of medicines. In inflammatory arthritis,
including rheumatoid arthritis, there is abundant evidence
implicating complement activation in humans and animal models.
Therefore, anti-complement agents might be beneficial as part
of clinical treatment. However, at present, there are still
no applicable agents for therapeutic regulation of excessive
complement activation in chronic disease. Novel agents in
development might be useful as a strategy to control complement
activation. Here I describe recent knowledge of the complement
system in inflammatory arthritis, the recent developments
in anti-complement agents and their considerable potential
for the future.
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