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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 19, 2006
Contents
Round and Round we Go: Cyclic Peptides in Disease Pp.
2221-2232
Maria Katsara, Theodore Tselios, Spyros Deraos, George Deraos,
Minos Matsoukas, Eliada Lazoura, John Matsoukas and Vasso
Apostolopoulos
[Abstract]
Gangliosides Potentially Inhibit Extracellular
Nucleotide Metabolism Pp. 2233-2239
Miki Hara-Yokoyama
[Abstract]
Regulation of Inflammatory Responses by Sensory
Neurons: Molecular Mechanism(s) and Possible Therapeutic Applications
Pp. 2241-2251
Kenji Okajima and Naoaki Harada
[Abstract]
Quantitative Structure Activity Relationships
as Useful Tools for the Design of New Adenosine Receptor Ligands.
1. Agonist Pp. 2253-2266
Maykel Pérez González, Carmen Terán,
Marta Teijeira and Aliuska Morales Helguera
[Abstract]
Molecular Mechanisms of Respiratory Virus-Induced
Asthma and COPD Exacerbations and Pneumonia Pp. 2267-2290
Gaetano Caramori, Kazuhiro Ito, Marco Contoli, Antonino
Di Stefano, Sebastian L. Johnston, Ian M. Adcock and Alberto
Papi
[Abstract]
IL-13: A Promising Therapeutic Target for Bronchial
Asthma Pp. 2291-2298
K. Izuhara, K. Arima, S. Kanaji, S. Ohta and T. Kanaji
[Abstract]
Can siRNA Technology Provide the Tools for Gene
Therapy of the Future? Pp. 2299-2307
Zs Rácz and P. Hamar
[Abstract]
Inhibitors of Cathepsin B Pp. 2309-2327
R. Frlan and S. Gobec
[Abstract]
Current Status and Future Prospective of Immunointervention
in Multiple Sclerosis Pp. 2329-2343
Guido Cavaletti
[Abstract]
Abstracts
[Back to top]
Round and Round we Go: Cyclic Peptides in Disease
Maria Katsara, Theodore Tselios, Spyros Deraos, George Deraos,
Minos Matsoukas, Eliada Lazoura, John Matsoukas and Vasso
Apostolopoulos
There is a need for novel drugs for the treatment
of infectious diseases, autoimmunity and cancer. Cyclic peptides
constitute a class of compounds that have made crucial contributions
to the treatment of certain diseases. Penicillin, Vancomycin,
Cyclosporin, the Echinocandins and Bleomycin are well-known
cyclic peptides. Cyclic peptides, compared to linear peptides,
have been considered to have greater potential as therapeutic
agents due to their increased chemical and enzymatic stability,
receptor selectively, and improved pharmacodynamic properties.
They have been used as synthetic immunogens, transmembrane
ion channels, antigens for Herpes Simplex Virus, potential
immunotherapeutic vaccines for diabetes and Experimental Autoimmune
Encephalomyelitis - an animal model of Multiple Sclerosis,
as inhibitors against α-amylase
and as protein stabilizers. Herein, we review important cyclic
peptides as therapeutic agents in disease.
[Back to top]
Gangliosides Potentially Inhibit Extracellular
Nucleotide Metabolism
Miki Hara-Yokoyama
Gangliosides are glycolipids that contain sialic
acid and they are mainly located on the outer leaflet of the
cellular plasma membrane of most vertebrate and some invertebrate
cells. Because they have structurally diverse, bulky and negatively
charged oligosaccharide moieties, gangliosides endow cell
membranes with unique molecular characteristics. Although
they are abundant in the central nervous system (CNS), the
complete loss of gangliosides in mice does not result in gross
morphological abnormalities of the CNS. However, mutant mice
develop neurodegenerative diseases and die soon after birth,
suggesting that gangliosides are required for the maintenance
and development of a stable CNS and are crucial to sustain
life. At the cellular level, gangliosides influence cell growth
and death, probably because they are involved in the lipid-mediated
assembly of signaling molecules such as growth factor receptors
or integrins on the membranes. This article addresses the
structural similarity between the tandem sialic acid residues
of gangliosides and nicotinamide adenine dinucleotide (NAD+)
determined from biochemical data showing that gangliosides
inhibit NAD+
glycohydrolase activity and theoretical considerations. An
essential feature of the structural similarity resides in
a negative charge cluster formed by the two carboxyl groups
in the tandem sialic acid residues and the diphosphate moiety
of NAD+.
The potential physiological role(s) of gangliosides on the
regulation of extracellular nucleotide metabolism are discussed.
[Back to top]
Regulation of Inflammatory Responses
by Sensory Neurons: Molecular Mechanism(s) and Possible Therapeutic
Applications
Kenji Okajima and Naoaki Harada
Capsaicin-sensitive sensory neurons are nociceptive
neurons that release calcitonin gene-related peptide (CGRP)
on activation. Since CGRP has potent vasodilatory activity,
it has long been considered to be involved in aggravation
of inflammation such as tissue hyperemia and edema. However,
since ablation of the sensory fibers can result in a marked
increase in the severity of inflammation and reperfusion-induced
tissue inflammatory responses are enhanced in congenital CGRP-knockout
mice, the sensory neurons have been shown to play a role in
the maintenance of tissue integrity by regulating local inflammatory
responses. We demonstrated in rodents that stimulation of
sensory neurons reduces hypertension, stress-induced gastric
mucosal injury, reperfusion-induced liver injury, and endotoxin-induced
shock responses by attenuating inflammatory responses such
as increases in both tissue levels of tumor necrosis factor
(TNF) and tissue accumulation of neutrophils. Attenuation
of inflammatory responses by sensory neuron activation can
be explained mainly by CGRP-induced increase in the endothelial
production of prostacyclin (PGI2).
Since inflammatory responses are critically involved in the
development of a wide variety of diseases, pharmacological
stimulation of sensory neurons might contribute to treatment
of various pathologic conditions. In this review, the authors
describe molecular mechanism(s) by which sensory neuron activation
inhibits TNF production, thereby attenuating inflammatory
responses. Furthermore, the authors discuss some clinically
useful therapeutic agents that are capable of activating sensory
neurons and raise the possibility that pharmacological stimulation
of sensory neurons is the new paradigm for future therapeutic
strategies.
[Back to top]
Quantitative Structure Activity Relationships
as Useful Tools for the Design of New Adenosine Receptor Ligands.
1. Agonist
Maykel Pérez González, Carmen Terán,
Marta Teijeira and Aliuska Morales Helguera
In order to minimize expensive drug failures it is essential
to determine the potential biological activity of new candidates
as early as possible. In view of the large libraries of nucleoside
analogues that are now being handled in organic synthesis,
the identification of a drugs biological activity is advisable
even before synthesis and this can be achieved using predictive
biological activity methods. In this sense, computer aided
rational drug design strategies like Quantitative Structure
Activity Relationships (QSAR) or docking approaches have emerged
as promising tools. Although a large number of in silico
approaches have been described in the literature for the prediction
of different biological activities, the use of traditional
QSAR applications in the development of new agonist molecules
with affinity toward adenosine receptors is scarce. This review
attempts to summarize the current level of knowledge concerning
computational affinity predictions for adenosine receptors
using QSAR models based on knowledge of the agonist ligands.
Several computational protocols and different 2D and 3D descriptors
have been described in the literature for these targets, but
more effort is still required in this area.
[Back to top]
Molecular Mechanisms of Respiratory
Virus-Induced Asthma and COPD Exacerbations and Pneumonia
Gaetano Caramori, Kazuhiro Ito, Marco Contoli,
Antonino Di Stefano, Sebastian L. Johnston, Ian M. Adcock
and Alberto Papi
Lower airways inflammation is a central feature
of many lung diseases, including asthma, chronic obstructive
pulmonary disease (COPD) and pneumonia. Although the specific
characteristics of the inflammatory responses and the site
of inflammation differ between one disease to another, they
always involve recruitment and activation of inflammatory
cells and changes in structural cells of the lung. Inflammatory
responses are associated with an increased expression of a
cascade of proteins including cytokines, chemokines, growth
factors, enzymes, adhesion molecules and receptors. In most
cases the increased expression of these proteins is the result
of enhanced gene transcription: many of these genes are not
expressed in normal cells under resting conditions but they
are induced in the inflammatory process in a cell-specific
manner. Transcription factors regulate the expression of many
pro-inflammatory genes and play a key role in the pathogenesis
of airway inflammation.
Many studies have suggested a role for viral infections not
only as a causative agent of pneumonia but also of asthma
and COPD exacerbations. In this review we will provide an
overview of the relationship between common respiratory viral
infections and the molecular mechanisms involved in the activation
of airway inflammation and on the regulation of transcription
factors in these inflammatory respiratory diseases. The relative
importance of each transcription factor will be certainly
greatly clarified in the next few years with the growing availability
of specific inhibitors capable of blocking activation of a
specific transcription factor. Clearly this is an exciting
new area of ongoing research with promising therapeutic potential.
[Back to top]
IL-13: A Promising Therapeutic Target
for Bronchial Asthma
K. Izuhara, K. Arima, S. Kanaji, S. Ohta and T. Kanaji
The incidence of allergic diseases has dramatically
increased in recent decades, especially in urban and industrialized
areas. It is important socially as well as medically to establish
more useful strategies to overcome allergic disorders. Bronchial
asthma is a complex disease characterized by airway inflammation
involving a Th2-cytokine, interleukin (IL)-13. A substantial
body of evidence has accumulated pointing to the pivotal role
of IL-13 in the pathogenesis of bronchial asthma, based on
mainly analyses of mouse models. In addition to such analyses,
the high expression of IL-13 in lesions and genetic association
of several genes coding IL-13 signaling molecules with bronchial
asthma have raised the possibility that IL-13 plays a pivotal
role in the onset or exacerbation of human bronchial asthma.
Therefore, IL-13 and its signal pathway are thought to be
promising targets to develop a therapeutic agent for bronchial
asthma. In this article, we describe how IL-13 is involved
in the pathogenesis of bronchial asthma and then how therapeutic
agents to block IL-13 signals are developed for bronchial
asthma.
[Back to top]
Can siRNA Technology Provide the Tools
for Gene Therapy of the Future?
Zs Rácz and P. Hamar
A new era in genetics has started 15 years ago,
when co-suppression in petunia has been discovered. Later,
co-suppression was identified as RNA interference (RNAi) in
many plant and lower eukaryote animals. Although an ancient
antiviral host defense mechanism in plants, the physiologic
role of RNAi in mammals is still not completely understood.
RNAi is directed by short interfering RNAs (siRNAs), one subtype
of short double stranded RNAs. In this review we summarize
the history and mechanisms of RNAi. We also aim to highlight
the correlation between structure and efficacy of siRNAs.
Delivery is the most important obstacle for siRNA based gene
therapy. Viral and nonviral deliveries are discussed. In
vivo delivery is the next obstacle to clinical trials
with siRNAs. Although hydrodynamic treatment is effective
in animals, it cannot be used in human therapy. One possibility
is organ selective catheterization. The known side effects
of synthesized siRNAs are also discussed. Although there are
many problems to face in this new field of gene therapy, successful
in vitro and in vivo experiments raise hope
for treating human disease with siRNA.
[Back to top]
Inhibitors of Cathepsin B
R. Frlan and S. Gobec
Cathepsin B is an abundant and ubiquitously
expressed cysteine peptidase of the papain family. It is involved
in many physiological processes, such as remodeling of the
extracellular matrix (wound healing), apoptosis, and activation
of thyroxine and renin. In addition to its physiological roles,
cathepsin B is important in many pathological processes, such
as inflammation, parasite infection and cancer, where it is
highly up-regulated. In cancer patients, elevated cathepsin
B activity correlates to poor therapy outcome. Therefore,
it is not surprising that the use of cathepsin B inhibitors
reduces both tumor cell motility and invasiveness in vitro.
This review summarizes recent developments in cathepsin B
inhibition. To date, numerous protein inhibitors of cathepsin
B have been described, some of which are of endogenous origin
and function as regulators of cathepsin B activity in the
cell, such as the cystatins. In addition, some exogenous protein
inhibitors of cathepsin B have been isolated from various
natural sources, and the use of X-ray crystal structures of
cathepsin B complexed with such protein inhibitors has resulted
in the design and synthesis of many new small-molecular-weight
compounds as inhibitors of cathepsin B. These synthetic compounds
generally contain an electrophilic functionality that reacts
with cathepsin B. In the present review, these inhibitors
are divided according to their mechanisms of action, as reversible
and irreversible, and then further subdivided into groups
for their full descriptions.
[Back to top]
Current Status and Future Prospective
of Immunointervention in Multiple Sclerosis
Guido Cavaletti
Multiple sclerosis (MS) is a complex neurological
disorder characterized by inflammation and degeneration of
the central nervous system, primarily involving the white
matter. On the basis of a wide body of evidence in experimental
models and in affected patients, several attempts to treat
MS using drugs which modulate immune reactions have been performed
or are currently ongoing. However, it should be stressed that
inflammation does not have only a detrimental effect in MS.
In fact, parts of the inflammatory events are crucial for
the control and conclusion of the acute phase of damage and
it is probable that they actually favor regeneration and recovery.
Due to the above, several trials with immunosuppressant drugs
failed or were suspended because of unexpected worsening of
the course of MS.
The knowledge of MS immunopathogenesis is so rapidly evolving
that any attempt to review it is in some way frustrating.
On the other hand, this evolution is at the basis of the several
new treatment options which can be hypothesized for this disease.
The current status of immunosuppression in MS and the possible
future development of MS treatment will be reviewed, with
particular reference to those treatments which have already
been tested in clinical trials and which are based on sound
evidence of a putative interference with specific events occurring
in MS, with the sparing of general immunity.
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