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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 11, 2007
Contents
Combined Biomarkers for Early Alzheimer Disease Diagnosis
Pp. 1171-1178
Barbara Borroni, Enrico Premi, Monica Di Luca and Alessandro
Padovani
[Abstract]
Modulation of Transcription by PARP-1: Consequences
in Carcinogenesis and Inflammation Pp. 1179-1187
R. Aguilar-Quesada, J.A. Muñoz-Gámez, D.
Martín-Oliva, A. Peralta-Leal, R. Quiles-Pérez,
J.M. Rodríguez –Vargas, M. Ruiz de Almodóvar,
C. Conde, A. Ruiz-Extremera and F.J Oliver
[Abstract]
Microglial Activation and its Implications in the
Brain Diseases Pp. 1189-1197
S. Thameem Dheen, Charanjit Kaur and Eng-Ang Ling
[Abstract]
Molecular Anatomy of the Brain Endothelial Barrier:
An Overview of the Distributional Features Pp. 1199-1206
Masaki Ueno
[Abstract]
Current Developments in the Synthesis and Biological
Activity of HIV-1 Double-Drug Inhibitors Pp. 1207-1220
Clare I. Muhanji and Roger Hunter
[Abstract]
A False Paradise - Mixed Blessings in the Protein
Universe: The Amyloid as a New Challenge in Drug Development
Pp. 1221-1230
Ludmilla Morozova-Roche and Mantas Malisauskas
[Abstract]
The Nuclear Envelope, a Key Structure in Cellular
Integrity and Gene Expression Pp. 1231-1248
V.L.R.M. Verstraeten, J.L.V. Broers, F.C.S. Ramaekers
and M.A.M. van Steensel
[Abstract]
Medicinal Chemistry and Emerging Strategies Applied
to the Development of Selective Estrogen Receptor Modulators
(SERMs) Pp. 1249-1261
Musiliyu A. Musa, M. Omar F. Khan and John S. Cooperwood
[Abstract]
Role of Micafungin in the Antifungal Armamentarium
Pp. 1263-1275
Fumiaki Ikeda, Shigeki Tanaka, Hidenori Ohki, Satoru Matsumoto,
Katsuyuki Maki, Masataka Katashima, David Barrett and Yoshiyasu
Aoki
[Abstract]
Abstracts
[Back to top]
Combined Biomarkers for Early Alzheimer Disease
Diagnosis
Barbara Borroni, Enrico Premi, Monica Di Luca and Alessandro
Padovani
Few public health problems have captured the attention of
the biomedical and lay communities alike as has Alzheimer
Disease (AD). Several questions remain still open in disease
management, as the necessity to delineate disease process
from “normal ageing”. In the last few years, Mild
Cognitive Impairment (MCI) has received significant attention,
thus it represents the major risk factor for AD. Not all people
diagnosed as having MCI, however, will develop AD, hence there
is a need to reliably predict progression.
To this aim, different biomarkers have been proposed with
the attempt to identify MCI people who already have pre-clinical
AD. Neuropsychological assessment, peripheral and CSF biomarkers
as well as neuroimaging findings (both structural and functional)
have reported variable accuracy values, but better results
have been obtained by combined biomarker approach.
In this review, we summarise the most recent findings on combined
biomarkers and their usefulness in clinical practice for the
early and preclinical diagnosis of AD.
[Back to top]
Modulation of Transcription by PARP-1: Consequences
in Carcinogenesis and Inflammation
R. Aguilar-Quesada, J.A. Muñoz-Gámez, D.
Martín-Oliva, A. Peralta-Leal, R. Quiles-Pérez,
J.M. Rodríguez –Vargas, M. Ruiz de Almodóvar,
C. Conde, A. Ruiz-Extremera and F.J Oliver
Post-translational modification of proteins by poly(ADP-ribosyl)ation
is involved in the regulation of a number of biological functions.
While an 18 member superfamily of poly(ADP-ribose) polymerases
(PARP)s has been described PARP-1 accounts for more than 90%
of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1
act as a DNA nick sensor and is activated by DNA breaks to
cleave NAD(+) into nicotinamide and ADP-ribose to synthesize
long branching poly(ADP-ribose) polymers (PAR) covalently
attached to nuclear acceptor proteins. Whereas activation
of PARP-1 by mild genotoxic stimuli facilitate DNA repair
and cell survival, severe DNA damage triggers different pathways
of cell death including PARP-mediated cell death through the
translocation of apoptosis inducing factor (AIF) from the
mitochondria to the nucleus. PAR and PARP-1 have also been
described as having a function in transcriptional regulation
through their ability to modify chromatin-associated proteins
and as a cofactor of different transcription factors, most
notably NF-κB
and AP-1. Pharmacological inhibition or genetic ablation of
PARP-1 not only provided remarkable protection from tissue
injury in various oxidative stress-related disease models
but it result in a clear benefit in the treatment of cancer
by different mechanisms including selective killing of homologous
recombination-deficient tumor cells, down regulation of tumor-related
gene expression and decrease in the apoptotic threshold in
the co-treatment with chemo and radiotherapy. We will summarize
in this review the current findings and concepts for the role
of PARP-1 and poly(ADP-ribosyl)ation in the regulation of
transcription, oxidative stress and carcinogenesis.
[Back to top]
Microglial Activation and its Implications in the
Brain Diseases
S. Thameem Dheen, Charanjit Kaur and Eng-Ang Ling
An inflammatory process in the central nervous system (CNS)
is believed to play an important role in the pathway leading
to neuronal cell death in a number of neurodegenerative diseases
including Parkinson’s disease, Alzheimer’s disease,
prion diseases, multiple sclerosis and HIV-dementia. The inflammatory
response is mediated by the activated microglia, the resident
immune cells of the CNS, which normally respond to neuronal
damage and remove the damaged cells by phagocytosis. Activation
of microglia is a hallmark of brain pathology. However, it
remains controversial whether microglial cells have beneficial
or detrimental functions in various neuropathological conditions.
The chronic activation of microglia may in turn cause neuronal
damage through the release of potentially cytotoxic molecules
such as proinflammatory cytokines, reactive oxygen intermediates,
proteinases and complement proteins. Therefore, suppression
of microglia-mediated inflammation has been considered as
an important strategy in neurodegenerative disease therapy.
Several anti-inflammatory drugs of various chemical ingredients
have been shown to repress the microglial activation and to
exert neuroprotective effects in the CNS following different
types of injuries. However, the molecular mechanisms by which
these effects occur remain unclear. In recent years, several
research groups including ours have attempted to explain the
potential mechanisms and signaling pathways for the repressive
effect of various drugs, on activation of microglial cells
in CNS injury. We provide here a comprehensive review of recent
findings of mechanisms and signaling pathways by which microglial
cells are activated in CNS inflammatory diseases. This review
article further summarizes the role of microglial cells in
neurodegenerative diseases and various forms of potential
therapeutic options to inhibit the microglial activation which
amplifies the inflammation-related neuronal injury in neurodegenerative
diseases.
[Back to top]
Molecular Anatomy of the Brain Endothelial Barrier:
An Overview of the Distributional Features
Masaki Ueno
The blood-brain barrier (BBB) impedes the influx of intravascular
compounds from the blood to the brain. The elements composing
the BBB are endothelial cells, pericytes and the end-feet
of astrocytes. Among them, the endothelial cell barrier line
is the most critical for preventing toxic substances from
entering the brain. In this review, we focus on the ultrastructural
distribution of important components in the intracellular
junction and cytoplasm of brain endothelial cells. The ultrastructural
distribution of tight junction-specific integral membrane
proteins such as occludin, junctional adhesion molecules,
claudin, peripheral zonula occludens protein-1 (ZO-1), adherens
junction-specific transmembrane protein cadherin, and adherens
junction-associated peripheral proteins α-catenin,
β-catenin,
and p120 catenin is reviewed. P-glycoprotein and some other
transporters recently discovered in endothelial cells prevent
several compounds from entering the brain parenchyma. It is
likely that the transient inhibition of P-glycoprotein by
antidepressants enables other medicines to enter the brain.
Vesicular transport with clathrin-mediated or adsorptive endocytosis
through endothelial cells is also critical for transportation
of blood-born substances from the bloodstream to the brain.
How medicines pass the BBB to reach the brain parenchyma is
discussed.
[Back to top]
Current Developments in the Synthesis and Biological
Activity of HIV-1 Double-Drug Inhibitors
Clare I. Muhanji and Roger Hunter
A combination of different HIV inhibitors into a single molecular
entity is a strategy that is growing in popularity in HIV-chemotherapy
research. The high levels of resistance elicited by both nucleoside
and non-nucleoside reverse transcriptase inhibitors has prompted
the design of double-drugs combining these two entities with
the aim of addressing the emergence of resistance. The strategy
involves combining two different inhibitors into a single
chemical entity via a linker, with the aim of improving the
physicochemical characteristics of the individual compounds.
Linkers may be sub-divided into cleavable and non-cleavable.
While the former result in regeneration of the parent drugs
of the double-drug once in the cell cytoplasm, the latter
type is designed to allow the double-drug to target two active
sites in a simultaneous or bifunctional fashion, which are
located in close proximity. The linkers have been attached
at the C-5', C-5 or N-3 positions of the nucleoside, and in
some of the substrates synthesized, a synergistic anti-HIV
activity has been observed. This review focuses on the design
and synthesis of anti-HIV double-drugs reported to date.
[Back to top]
A False Paradise - Mixed Blessings in the Protein
Universe: The Amyloid as a New Challenge in Drug Development
Ludmilla Morozova-Roche and Mantas Malisauskas
Significant advances in therapeutic applications of proteins
and peptides have brought new challenges in the field of drug
development. Ordered protein aggregation known as amyloid
formation has recently emerged as a universal phenomenon due
to extensive research in protein folding and amyloid diseases.
The amyloid represents a new generic structure characterized
by cross-β-sheet
formation in its core, which implies that any polypeptide
can adopt this conformation under amyloid-prone conditions.
Some widely-used biopharmaceuticals such as insulin, glucagon,
amylin and calcitonin have been shown to form amyloids and
this list may be significantly extended upon further research.
Compared to soluble precursor proteins and amorphous aggregates
amyloids gain new properties such as remarkable stability
and protease resistance, polymorphism, self-propagation via
seeding and cross-seeding, cytotoxicity and induced immunogenicity.
Some of them can be hazardous in biopharmaceutical applications.
The causes of amyloid aggregation and strategies for its prevention
are reviewed here. They utilize the current knowledge of amyloid
properties, structure-based design principles and protein
chemistry. Once these challenges are met, they will ultimately
lead to safer and surer pharmaceuticals.
[Back to top]
The Nuclear Envelope, a Key Structure in Cellular
Integrity and Gene Expression
V.L.R.M. Verstraeten, J.L.V. Broers, F.C.S. Ramaekers
and M.A.M. van Steensel
The envelope that encapsulates the cell nucleus has recently
gained considerable interest, as several clinical syndromes
are linked to mutations in its molecular components. Most
disorders recognized so far are caused by defects in the nuclear
lamins, building blocks of a filamentous network lining the
nucleoplasmic side of the inner nuclear membrane. Nuclear
lamins are the evolutionary precursors of cytoskeletal intermediate
filaments and associate in a head-to-tail manner into a stable
lamina at the nuclear periphery and into a more dispersed
structure in the nucleoplasm. Lamins have a scaffolding function
for several nuclear processes such as transcription, chromatin
organization and DNA replication, and maintain nuclear and
cellular integrity. Mutations in the LMNA gene, encoding
A-type lamins, can cause cardiac and skeletal muscle disease,
lipodystrophy and premature ageing phenotypes. Hence, the
integrity of the nuclear envelope seems essential for longevity.
Furthermore, the laminopathies provide evidence that metabolism
and ageing are as tightly linked in humans as they are in
model organisms such as C. elegans. In this review, we elaborate
on the structure and functions of nuclear lamins, the spectrum
of syndromes related to mutations in nuclear envelope components
and pathogenic concepts unifying these disorders.
[Back to top]
Medicinal Chemistry and Emerging Strategies Applied
to the Development of Selective Estrogen Receptor Modulators
(SERMs)
Musiliyu A. Musa, M. Omar F. Khan and John S. Cooperwood
Selective estrogen receptor modulators (SERMs), known previously
as “antiestrogens”, are a new category of therapeutic
agents used for the prevention and treatment of diseases such
as osteoporosis and breast cancer. SERMs act as ER-agonist
in some tissues while acting as ER-antagonist in others based
on conformational change of the receptors, particularly at
the helix 12. Currently, there are two classes of clinically
approved SERMs; triphenylethylene derivatives (e.g., tamoxifen)
and benzothiophene derivatives (e.g., raloxifene). Tamoxifen,
raloxifene and toremifene are the most widely used SERMs.
Tamoxifen, an antagonist of the breast tissue, is the first
clinically identified compound with noticeable SERM activity.
Although tamoxifen has been very successful in breast cancer
treatment, its agonistic effect on the uterus is said to be
associated with increase risk of developing endometrial cancer.
Ideally, it is presumed that SERMs should selectively act
as an agonist in the bone and brain while simultaneously acting
as an antagonist in the breast and uterus. Therefore, the
therapeutic goal of SERMs is the prevention of estrogen deficiency
diseases without promoting estrogen-associated tumor growth.
Therefore, the objective of this review is to summarize various
effects that have been applied in improving the tissue-selectivity
of SERMs, highlighting the emerging understanding of their
mechanism of actions in selected target tissues and the development
of the SERMs. The significance in recent discovery of selective
estrogen receptor alpha modulators, SERAMs will also be reviewed.
[Back to top]
Role of Micafungin in the Antifungal Armamentarium
Fumiaki Ikeda, Shigeki Tanaka, Hidenori Ohki, Satoru Matsumoto,
Katsuyuki Maki, Masataka Katashima, David Barrett and Yoshiyasu
Aoki
Serious infections caused by opportunistic molds remain a
major problem for public health. Immune deficiency following
organ transplantation and aggressive cancer treatment has
greatly increased the incidence of systemic mycoses, and invasive\
aspergillosis in patients with AIDS is associated with significant
morbidity and mortality. Amphotericin B is the first-line
therapy for systemic infection because of its broad-spectrum
and fungicidal activity. However, considerable side effects
limit its clinical utility. The echinocandins are large lipopeptide
molecules that inhibit the synthesis of 1,3-β-D-glucan,
a key component of the fungal cell wall. Three echinocandins
have reached the market, and some others are in early clinical
development. Caspofungin was the first echinocandin to be
licensed for clinical use in most countries. Micafungin is
licensed for clinical use in Japan, China, Taiwan, Jordan,
Korea, Hong-Kong and the US, and anidulafungin is currently
licensed in the US. The novel class of echinocandins represents
a milestone in antifungal drug research that has further expanded
our therapeutic options. Studies to date have shown that micafungin
exhibits extremely potent antifungal activity against clinically
important fungi, including Aspergillus and azole
resistant strains of Candida. In animal studies,
micafungin is as efficacious as amphotericin B with respect
to improvement of survival rate. Micafungin is also characterized
by a linear pharmacokinetic profile and substantially fewer
toxic effects. Micafungin is a poor substrate for the cytochrome
P450 enzymes, and compared to azoles, fewer drug interactions
are described. No dose adjustments of the drug are required
in the presence of mycophenolate mofetil, cyclosporin, tacrolimus,
prednisolone, or sirolimus. Strategies using this new echinocandin
agent will benefit a large number of patients with severe
immune dysfunction.
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