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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 21, 2007
Contents
Protein Kinases as Small Molecule Inhibitor Targets in Inflammation
Pp. 2214-2234
M. Gaestel, A. Mengel, U. Bothe and K. Asadullah
[Abstract]
Sublingual Allergen Immunotherapy: Immunological Mechanisms
and Prospects for Refined Vaccine Preparations Pp.
2235-2244
R.E. O’Hehir, A. Sandrini, G.P. Anderson and J.M.
Rolland
[Abstract]
CD4+CD25+ T Regulatory Cells
and TGF-β
in Mucosal Immune System: The Good and the Bad Pp.
2245-2249
WanJun Chen, Sylvain Perruche and Jun Li
[Abstract]
The Role of Lymphocytes in the Pathogenesis of Asthma
and COPD Pp. 2250-2256
Simonetta Baraldo, Kim Lokar Oliani, Graziella Turato,
Renzo Zuin and Marina Saetta
[Abstract]
Small Molecule CXCR4 Chemokine Receptor Antagonists:
Developing Drug Candidates Pp. 2257-2277
Abid Khan, John Greenman and Stephen J. Archibald
[Abstract]
Structure, Production and Function of Erythropoietin:
Implications for Therapeutical Use in Cardiovascular Disease
Pp. 2278-2287
D. Mocini, T. Leone, M. Tubaro, M. Santini and M. Penco
[Abstract]
Connexins as Precocious Markers and Molecular Targets
for Chemical and Pharmacological Agents in Carcinogenesis
Pp. 2288-2303
G. Pointis, C. Fiorini, J. Gilleron, D. Carette and D.
Segretain
[Abstract]
Recent Anti-Influenza Strategies in Multivalent
Sialyloligosaccharides and Sialylmimetics Approaches
Pp. 2304-2313
Xue-Long Sun
[Abstract]
Serum Cystatin C-A Useful Endogenous Marker of
Renal Function in Intensive Care Unit Patients at Risk for
or with Acute Renal Failure? Pp. 2314-2317
Annick A.N.M. Royakkers, Jeroen D.E. van Suijlen, Lieuwe
S. Hofstra, Michael A. Kuiper, Catherine S.C. Bouman, Peter
E. Spronk and Marcus J. Schultz
[Abstract]
Abstracts
[Back to top]
Protein Kinases as Small Molecule Inhibitor
Targets in Inflammation
M. Gaestel, A. Mengel, U. Bothe and K. Asadullah
The human kinome describes a major group of intracellular
signalling molecules. In the last few years, many molecules
in the group have become targets for therapeutic interventions.
Due to the conserved reaction mechanism of catalysis, protein
kinases seem well “drugable” by small molecular
weight inhibitors, thus opening the chance to novel oral bioavailable
drug development. A large number of small molecule weight
inhibitors for protein kinases have already been introduced
into research and these molecules are extensively analysed
in regard to their efficiency, potency and selectivity. Here
we summarise the use of small molecule protein kinase inhibitors
relevant for acute and chronic inflammation based on their
essential role in cellular signaling mechanisms in immune
cells such as macrophages, lymphoytes and granulocytes. We
describe the progress made to develop inhibitors against Toll-like
receptor associated kinases (IRAKs), against the MAPK kinase
kinases Cot/Tpl-2 and TAK1, against Inhibitor-κB
kinases (IKKs), against MAPK kinases (MEKs, MKKs), against
MAPKs (ERK2, p38, JNKs) and against their downstream kinases
MNK1 and MK2/3. This overview should help to keep up with
the fast developing field and the continuously growing number
of protein kinase inhibitors.
[Back to top]
Sublingual Allergen Immunotherapy: Immunological Mechanisms
and Prospects for Refined Vaccine Preparations
R.E. O’Hehir, A. Sandrini, G.P. Anderson
and J.M. Rolland
Allergic diseases constitute a major health issue worldwide.
Mainstay treatment constitutes allergen avoidance and pharmacotherapy
for symptom relief, but allergen immunotherapy offers advantages
of specific treatment with long lasting efficacy, and being
able to modify the course of the disease. Conventional immunotherapy
involves the subcutaneous injection of gradually increasing
amounts of allergen extract but the use of current whole allergen
extracts is restricted by the risk of adverse IgE-mediated
events especially for potent allergens such as peanut and
latex and for asthmatics. This has lead to interest in alternative
routes of immunotherapy. Oral tolerance is a well-documented
immune process and the sublingual route of administration
of allergen immunotherapy is attracting interest. Recent meta-analyses
show that sublingual allergen immunotherapy for grass pollen
and house dust mite allergy is clinically effective and safer
than injection immunotherapy. Some studies show SLIT induces
changes of T cell anergy, immune deviation, blocking antibodies,
and induction of regulatory T cells, as described for injection
immunotherapy pointing to the need to target allergen-specific
T cells, there is emergent evidence that the oral mucosa presents
distinct regulatory features. Evidence suggests that oral
dendritic cells play a key role in inducing tolerance especially
when allergen is taken up via Fc receptor bound IgE.
This suggests that although both would target aller-gen-specific
T cells, allergen formulations may differ with respect to
IgE epitopes for optimal SLIT compared with SCIT. Identification
of the molecular nature of the allergen-DC receptor interaction
is required to determine whether short peptides or recombinant
allergen preparations and of suitable adjuvants specifically
tailored for the sublingual route will allow the development
of improved allergen for-mulations and delivery strategies
for efficacy of treatment whilst decreasing IgE-mediated adverse
effects.
[Back to top]
CD4+CD25+ T Regulatory Cells
and TGF-β
in Mucosal Immune System: The Good and the Bad
WanJun Chen, Sylvain Perruche and Jun Li
Three major mucosal systems exist in the body, the oral-gastrointestinal,
the respiratory and the genitourinary systems. In particular,
the gastrointestinal (GI) tract contains the largest mucosal
surface in the body and is the major port of entry for foreign
antigens. Therefore, the gut immune system has to differentiate
to tolerate dietary antigens and expel infectious and harmful
pathogens. During the complex but well-orchestrated immune
responses in the mucosal system, T cells play a pivotal role
in both immunity and tolerance. Of many T cell subpopulations,
CD4+CD25+ T regulatory cells (Tregs)
are instrumental in regulation of immune responses in mucosea.
Among the multitude of cytokines and factors that are produced
in the gut, Transforming Growth Factor-beta (TGF-β
) is probably the most important one in influencing mucosal
T cell responses. The interaction and mutual regulation between
TGF-β
and CD4+CD25+ Tregs may be the key in
maintaining the balance between T cell immunity and tolerance
in mucosal system. In this article, we attempt to discuss
both beneficial and detrimental effects of TGF-β
and Tregs on oral tolerance, mucosal inflammation and autoimmunity,
colon cancer and HIV infection in the gut.
[Back to top]
The Role of Lymphocytes in the Pathogenesis of
Asthma and COPD
Simonetta Baraldo, Kim Lokar Oliani, Graziella Turato,
Renzo Zuin and Marina Saetta
Asthma and chronic obstructive pulmonary disease (COPD) are
two different inflammatory disorders of the lungs which share
a common functional abnormality, i.e. airflow limitation [1,2].
In asthma, airflow limitation is largely reversible, either
spontaneously or with treatment, and does not progress in
most cases [1]. On the other hand, airflow limitation in COPD
is usually progressive and poorly reversible [2].
In asthma, the chronic inflammation causes an associated increase
in airway responsiveness to a variety of stimuli, leading
to recurrent episodes of wheezing, breathlessness, chest tightness
and cough, particularly at night and in the early morning.
Many cells are involved in the inflammatory response in asthma
and, among these, CD4+ Type-2 lymphocytes, mast
cells and eosinophils are thought to play a crucial role.
In COPD, the poorly reversible airflow limitation is associated
with an abnormal inflammatory response of the lungs to noxious
particles or gases [2]. This chronic inflammation is characterized
by an increased number of CD8+ Type-1 T-lymphocytes
and macrophages in the lung tissue and neutrophils in the
airway lumen.
Lymphocytes, which are markedly different in the two inflammatory
conditions, play a crucial role in the pathogenesis of asthma
and COPD. In this review, we will discuss the current concepts
on the recruitment, homing and activity of lymphocytes in
these two respiratory diseases.
[Back to top]
Small Molecule CXCR4 Chemokine Receptor Antagonists:
Developing Drug Candidates
Abid Khan, John Greenman and Stephen J. Archibald
Chemokine receptors are a target of growing interest for new
therapeutic drugs, as their role in multiple disease states
has been demonstrated. The CXCR4/ CXCL12 pairing has been
implicated in HIV and cancer, as well as chronic inflammatory
diseases, including asthma and rheumatoid arthritis. HIV uses
CXCR4 or CCR5 receptors in the key binding step of the infection
process, leading to the idea that drugs could be developed
to block this interaction. Cancer metastasis has also been
linked to cellular communication via the chemokine
pathways and hence, receptor antagonists could potentially
inhibit this important pathway of disease progression. A wealth
of data concerning small molecule CXCR4 receptor antagonists
has been generated over the last few years, as a variety of
these small molecules have been tested, and the understanding
of structure activity relationships has improved.
Here, we review the developing area of small molecule CXCR4
antagonists and the rapidly increasing amount of data from
biological studies. Both peptidic and non-peptidic compounds
have been investigated. In particular, we focus on AMD3100
and bismacrocyclic analogues, the most extensively studied
class of CXCR4 antagonists, and the recent developments in
this area.
[Back to top]
Structure, Production and Function of Erythropoietin:
Implications for Therapeutical Use in Cardiovascular Disease
D. Mocini, T. Leone, M. Tubaro, M. Santini and
M. Penco
Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting
of 165 amino acids produced mainly in the kidney and in the
liver and regulating erythrocyitosis. It primarily acts on
erythroid precursor cell at colony-forming units-erythroid
stage inhibiting the apoptosis. EPO binds on a specific membrane
receptor thereby activating at least three specific intracellular
signaling pathways, such as phosphatidylinositol 3-kinase/
protein kinase B, Ras-mitogen-activated protein kinase and
some members of the signal transducers and activators of transcription
family.
In addition to kidney and liver, EPO mRNA has been detected
in other tissues; accordingly EPO receptor has been identified
in several type of cells and recent reports have suggested
new roles for EPO in non-haematopoietic tissues with a robust
evidence for neuroprotective and cardioprotective activity.
In different animal models, in vitro, in isolated
perfused heart and in vivo, recombinant human erythropoietin
protects heart from ischemia reperfusion injury and reduces
myocardial damage. EPO tissue protective activity can be separated
from erythropoietic activity. Molecules owing the first property
but not the second one have been described. In patients with
acute myocardial infarction serum EPO level correlates inversely
with infarct size. Acute coronary syndrome, extracorporeal
circulation and percutaneous coronary intervention are potential
fields of application for tissue protective EPO activity to
reduce myocardial damage, increase cardiac function ad improve
outcome.
[Back to top]
Connexins as Precocious Markers and Molecular Targets
for Chemical and Pharmacological Agents in Carcinogenesis
G. Pointis, C. Fiorini, J. Gilleron, D. Carette
and D. Segretain
Gap junctions, intercellular channels structured by the connexin
protein family, have been implicated in the control of cell
homeostasis, proliferation, differentiation and death. A loss
of the gap junction intercellular communication and/or connexin
dysfunction are typical features of cancer per se and have
been associated with the effect of many carcinogens. Indeed,
many early human neoplasia of various organs and human tumor
cell lines exhibit deficient connexin-mediated communication
expression mainly related, in a large number of observations,
with an aberrant cytoplasmic localization of this membranous
protein. Restoration of normal phenotype in transformed cells
by restoration of exogenous connexin gave rise to the concept
that connexins may act as tumor suppressors. However, the
mechanisms by which connexins mediate such a tumor suppressor
effect are multiple. They may result from: formation of functional
channels; hemichannels or are directly associated with connexin
expression. In addition, the literature shows that they may
be dependent upon the cell type and the connexin type. In
the present review, we analyze all these aspects of connexin/gap
junction involvement in the carcinogenesis process, in human
cancers and discuss the possibility of using connexins as
potential anti-oncogenic targets for cancer chemoprevention
and/or chemotherapy.
[Back to top]
Recent Anti-Influenza Strategies in Multivalent Sialyloligosaccharides
and Sialylmimetics Approaches
Xue-Long Sun
Sialic acid-containing oligosaccharides expressed on the respiratory
tract epithelial cell surface are involved in influenza virus
infection in both virus attaching and detaching processes.
Therefore, inhibition of sialic acid-binding processes provides
rational anti-influenza strategies. Previous exploring efforts
using monosaccharide sialic acid-bearing macromolecules provided
proof of concept for multivalent hemagglutinin inhibition.
However, the monosaccharide sialic acid cannot account for
the molecular determinant of virus receptor-binding specificity
in the context of the whole sialyloligosaccharide receptor.
On the other hand, neuraminidase inhibition efforts using
sialylmimetics have resulted into two antiinfluenza drugs,
zanamivir and oseltamivir, which have been shown to reduce
both the severity and duration of influenza illness. Nevertheless,
the usage of monomeric sialylmimetics requires relatively
large amounts of expensive compounds, which may also induce
virus resistance and side effect. Therefore, it is critical
to develop new antiinfluenza drugs and improve the current
antiinfluenza drugs. This review highlights recent explorations
of multivalent sialyloligosaccharides-based influenza virus
adhesion inhibition strategy and multivalent sialylmimetics-based
influenza virus detachment inhibition strategy for these efforts.
[Back to top]
Serum Cystatin C-A Useful Endogenous Marker of Renal
Function in Intensive Care Unit Patients at Risk for or with
Acute Renal Failure?
Annick A.N.M. Royakkers, Jeroen D.E. van Suijlen, Lieuwe
S. Hofstra, Michael A. Kuiper, Catherine S.C. Bouman, Peter
E. Spronk and Marcus J. Schultz
Critically ill patients are at high risk for developing acute
renal failure (ARF). The prevention of ARF is of outmost importance
in order to improve the increased morbidity and mortality
associated with ARF. Unfortunately, there is lack of adequate
endogenous markers that can identify renal dysfunction early
– this hampers timely application of measures to prevent
further renal damage. The use of exogenous markers of renal
function is not only time–consuming but also expensive,
and therefore can not be used on a regular basis in the intensive
care unit. Both the presently used endogenous and exogenous
markers are not reliable during continuous renal replacement
therapy (CRRT) because these markers are removed by the therapy
itself impeding early detection of recovering of renal function.
Cystatin C has been proposed as an alternative endogenous
marker of renal function for more than 15 years. In this manuscript
we review the literature on the role of cystatin C as marker
for renal function, focusing on the critically ill patient.
Serum cystatin C concentrations have been found to relate
to renal impairment and suggest that cystatin C is more sensitive
to detect mild decreases in GFR. Cystatin C could be an important
tool both to recognize early renal dysfunction and to identify
renal recovery while on CRRT in the critically ill patient,
however, we are in need of more studies.
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