|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 1, 2008
Contents
Modulation of Neuro-Inflammation and Vascular Response by
Oxidative Stress Following Cerebral Ischemia Reperfusion Injury
Pp. 1-14
Connie H.Y. Wong and Peter J. Crack
[Abstract]
Nuclear Magnetic Resonance Spectroscopy and Genetic
Disorders Pp. 15-36
R.A. Iles
[Abstract]
Virtual Screening and Its Integration with Modern
Drug Design Technologies Pp. 37-46
Rafael V.C. Guido, Glaucius Oliva and Adriano D. Andricopulo
[Abstract]
Aggresome Formation and Neurodegenerative Diseases:
Therapeutic Implications Pp. 47-60
J.A. Olzmann, L. Li and L.S. Chin
[Abstract]
Type 2 Diabetes and Oral Antihyperglycemic Drugs
Pp. 61-74
Cassia S. Mizuno, Amar G. Chittiboyina, Theodore W. Kurtz,
Harrihar A. Pershadsingh and Mitchell A. Avery
[Abstract]
Phytoecdysteroids and Anabolic-Androgenic Steroids
– Structure and Effects on Humans Pp. 75-91
Mária Báthori, Noémi Tóth,
Attila Hunyadi, Árpád Márki and Erno
Zádor
[Abstract]
Mammalian Cytosine DNA Methyltransferase Dnmt1:
Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and
RNA-directed DNA Methylation Pp. 92-106
Željko M. Svedružic
[Abstract]
Abstracts
[Back to top]
Modulation of Neuro-Inflammation and Vascular
Response by Oxidative Stress Following Cerebral Ischemia Reperfusion
Injury
Connie H.Y. Wong and Peter J. Crack
The mechanisms leading to cellular damage from ischemia-reperfusion
(I/R) injury are complex and multi-factorial. Accumulating
evidence suggests an important role for oxidative stress in
the regulation of neuro-inflammation following stroke. Gene
expression studies have revealed that the increase in oxygen
radicals post-ischemia triggers the expression of a number
of pro-inflammatory genes. These genes are regulated by the
transcription factor, nuclear factor-kappa-B (NF-κB)
which is redox-sensitive. It is hypothesised that changes
in the oxidative state may modulate alterations in the neuro-inflammatory
response following an I/R injury. Furthermore, NF-κB
is involved in the transcriptional regulation of adhesion
molecules, which play an important role in leukocyte-endothelium
interactions. Recent studies have demonstrated that adhesion
molecule-mediated leukocyte recruitment is associated with
increased tissue damage in stroke, while mice lacking key
adhesion molecules conferred neuro-protection. Nevertheless,
the involvement of oxidative stress in leukocyte recruitment
and the subsequent regulated cell injury is yet to be elucidated.
While leukocyte infiltration into the ischemic brain is detrimental,
leukocyte accumulation in the microvasculature was shown to
be one of the many factors implicated in reduced reperfusion.
Although this “no-reflow” phenomenon was confirmed
in a variety of animal models of cerebral ischemia, the exact
mechanism is still uncertain. This review aims to highlight
the impact that oxidative stress has in the regulation of
post-ischemic neuro-inflammation and the implication for the
cerebral microvasculature after injury.
[Back to top]
Nuclear Magnetic Resonance Spectroscopy and Genetic Disorders
R.A. Iles
Nuclear magnetic resonance spectroscopy has been exploited
to study the metabolic characteristics (phenotype) of genetic
dis-orders by taking advantage of some unique characteristics
of the technique.
The first application, metabolic profiling for diagnosis and
therapeutic monitoring in vitro, demonstrates the
exceptional diversity of metabolites detected by NMR, and
has resulted in new interest in significant metabolites largely
ignored previously because other techniques do not detect
them, e.g. betaine and creatine. Moreover, previously ‘unknown'
genetic disorders have been detected and characterised The
same NMR technique can be effectively exploited for metabolic
profiling of mutation models in yeast and mice, leading to
a prominent role in the development of large scale metabolomic
profiling to link genomic information with phenotype.
The second application, magnetic resonance spectroscopy (MRS),
exploits the unique possibility of studying human metabolism
in vivo, which permits intracellular rather than
extracellular metabolic profiling. When it is possible to
detect the precise diagnostic metabolites in vivo,
investigators have been able to link clinical status with
cellular biochemistry, sometimes questioning the clinical
value of extracellular (plasma) metabolite measurements. Thus,
claims have been made that brain phenylalanine concentrations
match more closely the clinical status of patients with phenylketonuria.
These studies in vivo have also led to new diagnoses
e.g. the disorders of creatine synthesis and transport, highlighting
a new category of brain syndromes.
Future applications of NMR are cautiously considered as they
are critically dependent on continued improvement in resolution
and sensitivity in turn generated by developments in magnet
design and higher fields.
[Back to top]
Virtual Screening and Its Integration with Modern
Drug Design Technologies
Rafael V.C. Guido, Glaucius Oliva and Adriano D. Andricopulo
Drug discovery is a highly complex and costly process,
which demands integrated efforts in several relevant aspects
involving innovation, knowledge, information, technologies,
expertise, R&D investments and management skills. The
shift from traditional to genomics- and proteomics-based drug
research has fundamentally transformed key R&D strategies
in the pharmaceutical industry addressed to the design of
new chemical entities as drug candidates against a variety
of biological targets. Therefore, drug discovery has moved
toward more rational strategies based on our increasing understanding
of the fundamental principles of protein-ligand interactions.
The combination of available knowledge of several 3D protein
structures with hundreds of thousands of small-molecules have
attracted the attention of scientists from all over the world
for the application of structure- and ligand-based drug design
approaches. In this context, virtual screening technologies
have largely enhanced the impact of computational methods
applied to chemistry and biology and the goal of applying
such methods is to reduce large compound databases and to
select a limited number of promising candidates for drug design.
This review provides a perspective of the utility of virtual
screening in drug design and its integration with other important
drug discovery technologies such as high-throughput screening
(HTS) and QSAR, highlighting the present challenges, limitations,
and future perspectives in medicinal chemistry.
[Back to top]
Aggresome Formation and Neurodegenerative Diseases:
Therapeutic Implications
J.A. Olzmann, L. Li and L.S. Chin
Accumulation of misfolded proteins in proteinaceous inclusions
is a prominent pathological feature common to many age-related
neurodegenerative diseases, including Parkinson's disease,
Alzheimer's disease, Huntington’s disease, and amyotrophic
lateral sclerosis. In cultured cells, when the production
of misfolded proteins exceeds the capacity of the chaperone
refolding system and the ubiquitin-proteasome degradation
pathway, misfolded proteins are actively transported to a
cytoplasmic juxtanuclear structure called an aggresome. Aggresome
formation is recognized as a cytoprotective response serving
to sequester potentially toxic misfolded proteins and facilitate
their clearance by autophagy. Recent evidence indicates that
aggresome formation is mediated by dynein/dynactin-mediated
microtubule-based transport of misfolded proteins to the centrosome
and involves several regulators, including histone deacetylase
6, E3 ubiquitin-protein ligase parkin, deubiquitinating enzyme
ataxin-3, and ubiquilin-1. Characterization of the molecular
mechanisms underlying aggresome formation and its regulation
has begun to provide promising therapeutic targets that may
be relevant to neurodegenerative diseases. In this review,
we provide an overview of the molecular machinery controlling
aggresome formation and discuss potential useful compounds
and intervention strategies for preventing or reducing the
cytotoxicity of misfolded and aggregated proteins.
[Back to top]
Type 2 Diabetes and Oral Antihyperglycemic Drugs
Cassia S. Mizuno, Amar G. Chittiboyina, Theodore W. Kurtz,
Harrihar A. Pershadsingh and Mitchell A. Avery
Type II diabetes is a heterogeneous disease where environment
and genetics are important factors for the expression of the
disease. The high cost for treating complications of diabetes
is a burden for public health systems and governments worldwide.
Type II diabetes has been causing debilitation worldwide for
many decades, and a single drug that safely treats the disease
has yet to be discovered. Sulfonylureas, biguanides, α-glucosidase,
meglitinides, DPP-4 inhibitors and thiazolidinediones are
among the classes of oral hypoglycemic drugs available to
treat Type II diabetes, but concerns exist regarding safety
and efficacy of these drugs. In this article we present the
pros and cons of the six classes and discuss some of the latest
advances towards the development of new drugs for the treatment
of Type II diabetes.
[Back to top]
Phytoecdysteroids and Anabolic-Androgenic Steroids
– Structure and Effects on Humans
Mária Báthori, Noémi Tóth,
Attila Hunyadi, Árpád Márki and Erno
Zádor
Phytoecdysteroids are structural analogs of the insect
molting hormone ecdysone. Plants comprise rich sources of
ecdysteroids in high concentration and with broad structural
diversity. Ecdysteroids have a number of proven beneficial
effects on mammals but the hormonal effects of ecdysteroids
have been proven only in arthropods. Their structures are
somewhat similar to those of the vertebrate steroid hormones
but there are several structural differences between the two
steroid groups. Despite of these essential structural differences,
ecdysteroids exert numerous effects in vertebrates that are
similar to those of vertebrate hormonal steroids, and they
may serve as effective anabolic, hepatoprotective, immunoprotective,
antioxidant and hypoglycemic agents.
Ecdysteroids do not bind to the cytosolic steroid receptors,
instead, they are likely to influence signal transduction
pathways, like the anabolic steroids, possibly via
membrane bound receptors.
The application of phytoecdysteroids is a promising alternative
to the use of anabolic-androgenic steroids because of the
apparent lack of adverse effects. The prospective use of phytoecdysteroids
may extend to treatments of pathological conditions where
anabolic steroids are routinely applied. One of the most cited
aspects of phytoecdysteroid application (on the Internet)
is the increase of muscle size. However in this field too
stringent research is needed as an adequate cytological explanation
is not yet available for the anabolic.
This paper reports on the most important structural differences
between androgenic hormones, their synthetic analogs and ecdysteroids.
The anabolic/hormonal effects and the possible mechanisms
of action of these compounds are also discussed as concerns
the skeletal muscle.
[Back to top]
Mammalian Cytosine DNA Methyltransferase Dnmt1: Enzymatic
Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed
DNA Methylation
Željko M. Svedružic
This is a review of the enzymatic mechanism of DNA methyltransferase
Dnmt1 and analysis of its implications on regulation of DNA
methylation in mammalian cells and design of novel mechanism-based
inhibitors. The methylation reaction by Dnmt1 has different
phases that depend on DNA substrate and allosteric regulation.
Consequently, depending on the phase, the differences in catalytic
rates between unmethylated and pre-methylated DNA can vary
between 30-40 fold, 3-6 fold or only 1 fold. The allosteric
site and the active site can bind different molecules. Allosteric
activity depends on DNA sequence, methylation pattern and
DNA structure (single stranded vs. double stranded).
Dnmt1 binds poly(ADP-ribose) and some RNA molecules. The results
on kinetic preferences, allosteric activity and binding preference
of Dnmt1 are combined together in one comprehensive model
mechanism that can address regulation of DNA methylation in
cells; namely, inhibition of DNA methylation by poly(ADP-ribose),
RNA-directed DNA methylation by methylated and unmethylated
non-coding RNA molecules, and transient interactions between
Dnmt1 and genomic DNA. Analysis of reaction intermediates
showed that equilibrium between base-flipping and base-restacking
events can be the key mechanism in control of enzymatic activity.
The two events have equal but opposite effect on accumulation
of early reaction intermediates and methylation rates. The
accumulation of early reaction intermediates can be exploited
to improve the current inhibitors of Dnmt1 and achieve inhibition
without toxic modifications in genomic DNA. [1,2-dihydropyrimidin-2-one]-5-methylene-(methylsulfonium)-adenosyl
is described as the lead compound.
|
