|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 22, 2007
Contents
Neurotrophic Factors – A Tool for Therapeutic Strategies
in Neurological, Neuropsychiatric and Neuroimmunological Diseases?
Pp. 2318-2329
O. Schulte-Herbrüggen, A. Braun, S. Rochlitzer, M.C.
Jockers Scherübl and R. Hellweg
[Abstract]
Noradrenaline in Parkinson's Disease: From Disease
Progression to Current Therapeutics Pp. 2330-2334
Francesco Fornai, Adolfo Bandettini di Poggio,
Antonio Pellegrini, Stefano Ruggieri and Antonio Paparelli
[Abstract]
Design, Synthesis, and Structure-Activity Relationship
Study of Peroxisome Proliferator-Activated Receptor (PPAR)
δ-Selective
Ligands Pp. 2335-2343
Hiroyuki Miyachi
[Abstract]
Hydrogen/Deuterium Exchange-Mass Spectrometry: A Powerful
Tool for Probing Protein Structure, Dynamics and Interactions
Pp. 2344-2358
Yuko Tsutsui and Patrick L. Wintrode
[Abstract]
Lymphatic Endothelial Cells, Inflammatory Lymphangiogenesis,
and Prospective Players Pp. 2359-2368
R.C. Ji
[Abstract]
Apoptosis: Potential Therapeutic Targets for New Drug
Discovery Pp. 2369-2379
Snehasis Jana and Jyoti Paliwal
[Abstract]
A Novel Functional Approach Toward Identifying Definitive
Drug Targets Pp. 2380-2392
Ranadhir Dey, Srijit Khan and Bhaskar Saha
[Abstract]
Homocysteine and Cerebral Stroke in Developing Countries
Pp. 2393-2401
Rita Christopher, D. Nagaraja and S.K. Shankar
[Abstract]
Serum Microbial- and Host-Derived Markers of Periodontal
Diseases: A Review Pp. 2402-2412
Pirkko J. Pussinen, Susanna Paju, Päivi
Mäntylä and Timo Sorsa
[Abstract]
The Role of Zebrafish in Chemical Genetics Pp.
2413-2420
Joachim Berger and Peter Currie
[Abstract]
Abstracts
[Back to top]
Neurotrophic Factors – A Tool for Therapeutic
Strategies in Neurological, Neuropsychiatric and Neuroimmunological
Diseases?
O. Schulte-Herbrüggen, A. Braun, S. Rochlitzer, M.C.
Jockers Scherübl and R. Hellweg
Nerve growth factor (NGF) and brain-derived neurotrophic factor
(BDNF) belong to the protein family of neurotrophins. They
both display profound neuromodulatory functions and are essentially
involved in the survival and homeostatic maintenance of central
and peripheral neurons during development and adulthood. Moreover,
NGF and BDNF are known to modulate immune cell function and
thus serve as mediators in the reciprocal cross talk between
neurons and immune cells. Neurotrophic factors have been implicated
in pathophysiological mechanisms of many diseases of the nervous
and the immune system, such as amyotrophic lateral sclerosis
(ALS), Alzheimer’s disease (AD), neuropathy, pain, allergic
bronchial asthma (BA) and neurotrophic keratitis. For all
these diseases research has reached the point of creating
strategies for therapeutic intervention with neurotrophins.
In this review, we present an overview of the pathophysiology,
therapeutic interventions and strategies concerning NGF and
BDNF in the mentioned diseases.
[Back to top]
Noradrenaline in Parkinson's Disease: From Disease
Progression to Current Therapeutics
Francesco Fornai, Adolfo Bandettini di Poggio,
Antonio Pellegrini, Stefano Ruggieri and Antonio Paparelli
The loss of the neurotransmitter noradrenaline occurs constantly
in Parkinson’s disease. This is supposed to worsen disease
progression, either by increasing the vulnerability of dopamine-containing
neurons or by reducing the recovery once they are damaged.
Novel data also show that the loss of noradrenergic innervation
facilitates the onset of dyskinesia occurring in Parkinsonian
patients during dopamine replacement therapy.
In the first part of the manuscript we review the evidence
showing the loss of the noradrenergic system as an early event
in the natural history of Parkinsonism. This evidence is discussed
in light of novel reports showing the deleterious effects
produced by the noradrenergic deficit on the survival of nigral
dopamine neurons. In particular, we analyze the biochemical
and morphological changes produced in the nigrostriatal system
by the loss of endogenous noradrenaline. In a dedicated paragraph
we specifically evaluate the cross affinity between dopamine
and noradrenaline systems. In fact, this is critical during
dopamine/noradrenaline replacement therapy in Parkinson’s
disease.
In the last part, we overview novel therapeutic approaches
aimed at restoring the activation of noradrenaline receptors
to reduce the dyskinesia occurring in the treatment of Parkinson’s
disease.
[Back to top]
Design, Synthesis, and Structure-Activity Relationship
Study of Peroxisome Proliferator-Activated Receptor (PPAR)
δ-Selective
Ligands
Hiroyuki Miyachi
Improvements in our understanding of the functions of peroxisome
proliferator-activated receptor (PPAR) subtypes as master
regulators of many biological functions have made it possible
to develop novel PPAR ligands with characteristic subtype
selectivity as biochemical tools and/or candidatedrugs for
the treatment of PPAR-dependent diseases such as metabolic
syndrome, which includes type II diabetes, dyslipidemia, obesity,
hypertension, and inflammation. Based on the findings that
the glitazone-class antidiabetic agents, and fibrate-class
antidyslipidemic agents are ligands of PPARγ
and PPARα
respectively, much research interest has been focused on these
two subtypes as therapeutic targets for the treatment of type
II diabetes and dyslipidemia. In contrast, research interest
in PPARδ
has been limited. However, since 2001, the availability of
PPARδ
knockout animals and selective ligands has led to the uncovering
of possible roles of PPARδ
in fatty acid metabolism, insulin resistance, reverse cholesterol
transport, inflammation, and so on. It has become clear that
ligands able to modulate PPARδ-mediated
pathways are candidates for the treatment of altered metabolic
function. This review focuses on recent medicinal chemical
studies to identify PPARδ-selective
agonists.
[Back to top]
Hydrogen/Deuterium Exchange-Mass Spectrometry: A Powerful
Tool for Probing Protein Structure, Dynamics and Interactions
Yuko Tsutsui and Patrick L. Wintrode
Knowledge of the structure and dynamics of proteins and protein
assemblies is critical both for understanding the molecular
basis of physiological and patho-physiological processes and
for guiding drug design. While X-ray crystallography and nuclear
magnetic resonance spectroscopy are both excellent techniques
for this purpose, both suffer from limitations, including
the requirement for high quality crystals and large amounts
of material. Recently, hydrogen/deuterium exchange measured
using mass spectrometry (HXMS) has emerged as a powerful new
tool for the study of protein structure, dynamics and interactions
in solution. HXMS exploits the fact that backbone amide hydrogens
can exchange with deuterium when a protein is incubated in
D2O, and that the rate of
the exchange process is highly dependent on the local structural
environment. Several features of HXMS make it an especially
attractive approach, including small sample requirements and
the ability to study extremely large protein assemblies that
are not amenable to other techniques. Here, we provide an
overview of HXMS and describe several recent applications
to problems of medical interest. After reviewing the molecular
basis of the H/D exchange process, the different steps of
the HXMS experiment – labeling, rapid proteolysis, fragment
separation and mass measurement – are described, followed
by a discussion of data analysis methods. Finally, we describe
recent results on the application of HXMS to 1) mapping drug/inhibitor
binding sites and detecting drug induced conformational changes,
2) studying viral capsid structure and assembly, and 3) characterizing
the structure of pathological protein conformations, specifically
amyloid fibrils.
[Back to top]
Lymphatic Endothelial Cells, Inflammatory Lymphangiogenesis,
and Prospective Players
R.C. Ji
De novo lymphangiogenesis influences different pathological
courses via modulating tissue fluid homeostasis,
macromolecule absorption, and leukocyte transmigration. During
the past decade, improved understanding of lymphatic biology,
especially VEGF-C/-D/VEGFR-3-mediating lymphangiogenesis has
substantially promoted clinical research in lymphatic insufficiency.
The role of lymphan-giogenesis in the setting of the inflammatory
processes observed in transplants, inflamed cornea, wound
healing, acquired lymphedema and tumor invasion, however,
remains to be elucidated. The chemokine family of peptide
chemoattractants and other mediators, e.g., CCL21-CCR7, D6,
NF-κB
and TNF-α
may be important contributors to pathophysiological changes
of lymphatic endothelial cells (LECs) and inflammatory lymphangiogenesis.
Dendritic cells and macrophages may also involve in LEC proliferation
and differentiation. Increased knowledge of LEC-specific modulators
in inflammatory microenvironment is vital for prevention and
treatment of lymphatic-associated diseases.
[Back to top]
Apoptosis: Potential Therapeutic Targets for New Drug
Discovery
Snehasis Jana and Jyoti Paliwal
Apoptosis is involved in a wide range of pathologic conditions,
including neurodegenerative, autoimmune diseases, cardiovascular
diseases and cancer. Therefore, the ability to understand
and manipulate the cell death machinery is an obvious goal
of medical research. Novel therapeutic approaches to modulate
disease by regulating apoptosis are being tested in preclinical
and clinical settings. Approaches include the traditional
use of small molecules to target specific players in the apoptosis
cascade. As our understanding of apoptosis increases, further
opportunities will arise for tailor-made therapies that will
result in improved clinic. From variety of compounds are discovered
in this field and only few are found in the preclinical and
clinical trials. The lack of specific potent nonpeptide apoptosis
inducers and/or inhibitors has limited for a long time the
clinical investigation of this target. But in the last few
years the renewed interest of pharmaceutical companies has
been giving a strong impulse to the research in this area.
This review considers the molecular mechanisms of apoptosis
and their interaction in regulation of apoptosis. We also
focus on recent developments of nonpeptide apoptosis modulators
and their progress in drug lead discovery.
[Back to top]
A Novel Functional Approach Toward Identifying Definitive
Drug Targets
Ranadhir Dey, Srijit Khan and Bhaskar Saha
The process of developing drugs dates to antiquity. The herbal
formulations during the old days were more traditional than
with any scientific rationale. As different branches of physics,
chemistry and biology started revealing the physiological
processes in molecular details and as the sophisticated methods
for probing into these phenomena were innovated, the processes
of drug development changed significantly. However, the very
first step in the process which is defining a drug target
remains a major hurdle. The classical methods that predate
the functional genomics and proteomics involve a cumbersome,
painstaking detailing of a given enzyme or a receptor, followed
by its validation as a target. The sophisticated methods in
the post-genomic and proteomic era reduced the time taken
to define targets, but the speed of drug discovery is not
necessarily as quick as it promised. This is primarily due
to prolific predictions pressing validation too hard, although
both non-robotic and robotic high throughput screenings match
with the requirement. Since these drugs target pathogens,
a serious disadvantage with these methodologies is the emergence
of drug resistance. Therefore, we propose a functional approach
whereby the host-pathogen interaction is studied to find out
the alterations in immune responses, the profile of host gene
expression and activation of cell signaling molecules, the
kinases in particular. Such interactions often induce the
expression of those genes and activation of those proteins
which are required for their survival. We demonstrate that
reversal of such profiles of gene expression and protein activation
ameliorates the infection. Therefore, those gene products
and the kinases with pro-parasitic functions can serve as
targets.
[Back to top]
Homocysteine and Cerebral Stroke in Developing Countries
Rita Christopher, D. Nagaraja and S.K. Shankar
Two-thirds of stroke deaths worldwide occur in developing
countries. The higher prevalence of undernutritional states
and parasitic infestations in many of these countries could
lead to vitamin B12 and folate
deficiencies. Hyperhomocysteinemia, a proxy measure for the
nutritional status of B vitamins, has been reported in many
developing countries and is found to be associated with nutrition-related
low plasma folate and vitamin B12.
Several epidemiological observations have linked hyperhomocysteinemia
to increased risk for stroke. The exact molecular mechanism
by which homocysteine promotes atherothrombosis is not clear,
although several possible roles have been suggested. Homocysteine
is believed to cause atherogenesis and thrombogenesis via
endothelial damage, focal vascular smooth muscle proliferation
probably causing irregular vascular contraction, and coagulation
abnormalities. Supplementation with the nutrient cofactors
required for optimal functioning of the homocysteine metabolic
pathways significantly impacts plasma homocysteine levels,
and offers a new integrated possibility for prevention of
stroke in the underdeveloped and rapidly developing countries.
[Back to top]
Serum Microbial- and Host-Derived Markers of Periodontal
Diseases: A Review
Pirkko J. Pussinen, Susanna Paju, Päivi
Mäntylä and Timo Sorsa
Periodontitis is bacterial infection of tooth-supporting tissues
leading to inflammation and, subsequently, to loss of teeth.
It is one of the most common infections worldwide. Recent
studies have shown that periodontal infection may pose a threat
to general health by increasing the risk of cardiovascular
and lung diseases, and preterm labour. Thus, useful markers
of systemic exposure to periodontitis are needed. Markers
of periodontitis in serum include those derived directly from
periodontopathic pathogens and those originating from the
host defence and immune mechanisms. Periodontitis is associated
with endotoxemia, which can be directly measured as elevated
concentrations of lipopolysaccharide (LPS) in periodontitis
patients compared with healthy subjects. Also indirect methods
determining endotoxemia, such as elevated concentrations of
serum LPS binding protein, soluble CD14, and antibodies to
LPS of periodontal pathogens have been reported. Surrogate
measures of the host response against periodontal infection,
such as matrix metalloproteinases, cytokines, chemokines,
inflammation markers, antiphospholipid antibodies, and antibodies
to periodontal pathogens, have been used. Of these, however,
only antibodies to periodontal pathogens may be seen as specific
markers of systemic exposure to periodontopathic pathogens.
In this paper we describe and discuss serum markers of periodontitis
that have been used for research purposes and/or to support
diagnostics. Based on literature review, we encourage research
and development of serum screening methods for periodontitis
that could be used by general physicians.
[Back to top]
The Role of Zebrafish in Chemical Genetics
Joachim Berger and Peter Currie
The identification and exploration of new drug candidates
to fight diseases is a major imperative for improving human
health. The traditional mechanism utilised to identify new
compounds with therapeutic potential has been to systematically
analyse large libraries of small molecules for lead compounds
with a desired bioactivity in protein or cell based assays.
Identified lead compounds were subsequently assessed for their
potential as lead drugs. In the last few years, small molecule
screens were also carried out in vivo, on whole organisms
such as the zebrafish. Cost efficient maintenance together
with abundant manipulatory techniques and molecular tools
have made the zebrafish a preferred system in which to perform
large-scale screens. Numerous studies have revealed that zebrafish
mutants can accurately model many aspects of human diseases.
Therefore, small molecules identified in zebrafish-based screens
can be particularly valuable in identifying lead compounds
with direct therapeutic relevance to specific human disease
states. Here, we review the role of zebrafish-based screens
in the emerging field of chemical genetics.
|
