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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 28, 2007
Contents
Mannose 6-Phosphate Receptor Targeting and its Applications
in Human Diseases Pp. 2945-2953
M. Gary-Bobo, P. Nirdé, A. Jeanjean, A. Morère
and M. Garcia
[Abstract]
The Molecular Basis of Susceptibility to Infection in Liver
Cirrhosis Pp. 2954-2958
Norberto C. Chavez-Tapia, Aldo Torre-Delgadillo, Felix
I. Tellez Avila and Misael Uribe
[Abstract]
Microtubule-Stabilizing Natural Products as Promising
Cancer Therapeutics Pp. 2959-2967
Brian M. Gallagher Jr.
[Abstract]
Oxidative RNA Damage and Neurodegeneration Pp. 2968-2975
A. Nunomura, P.I. Moreira, A. Takeda, M.A. Smith and G.
Perry
[Abstract]
Towards the Development of a Broadly Protective Group A Streptococcal
Vaccine Based on the Lipid-Core Peptide System Pp.
2976-2988
C. Olive, P.M. Moyle and I. Toth
[Abstract]
Serotonin and Cognitive Flexibility: Neuroimaging
Studies into the Effect of Acute Tryptophan Depletion in Healthy
Volunteers Pp. 2989-2995
E.A.T. Evers, F.M. van der Veen, D. Fekkes and J. Jolles
[Abstract]
Recent Developments in Studies of l-Stepholidine
and its Analogs: Chemistry, Pharmacology and Clinical Implications
Pp. 2996-3002
Jiao Mo, Yang Guo, Yu-She Yang, Jing-Shan Shen, Guo-Zhang
Jin and Xuechu Zhen
[Abstract]
Predictive Models for hERG Channel Blockers: Ligand
Based and Structure-Based Approaches Pp. 3003-3026
Khac-Minh Thai and Gerhard F. Ecker
[Abstract]
Calcium Sensing Receptor Activators: Calcimimetics
Pp. 3027-3034
Paul E. Harrington and Christopher Fotsch
[Abstract]
Tamoxifen Resistance and Epigenetic Modifications
in Breast Cancer Cell Lines Pp.
3035-3043
Eric Badia, Joan Oliva, Patrick Balaguer and Vincent Cavaillès
[Abstract]
Regulation of Mast Cell Development by Inflammatory
Factors Pp. 3044-3050
Zhi-Qing Hu, Wei-Hua Zhao and Tadakatsu Shimamura
[Abstract]
Abstracts
[Back to top]
Mannose 6-Phosphate Receptor Targeting and
its Applications in Human Diseases
M. Gary-Bobo, P. Nirdé, A. Jeanjean, A. Morère
and M. Garcia
The cation-independent mannose 6-phosphate receptor is
a multifunctional protein which binds at the cell surface
to two distinct classes of ligands, the mannose 6-phosphate
(M6P) bearing proteins and IGF-II. Its major function is to
bind and transport M6P-enzymes to lysosomes, but it can also
modulate the activity of a variety of extracellular M6P-glycoproteins
(i.e., latent TGFβ
precursor, urokinase-type plasminogen activator receptor,
Granzyme B, growth factors, Herpes virus). The purpose of
this review is to highlight the synthesis and potential use
of high affinity M6P analogues able to target this receptor.
Several M6P analogues with phosphonate, carboxylate or malonate
groups display a higher affinity and a stronger stability
in human serum than M6P itself. These derivatives could be
used to favour the delivery of specific therapeutic compounds
to lysosomes, notably in enzyme replacement therapies of lysosomal
diseases or in neoplastic drug targeting. In addition, their
potential applications in preventing clinical disorders, which
are associated with the activities of other M6P-proteins involved
in wound healing, cell growth or viral infection, will be
discussed.
[Back to top]
The Molecular Basis of Susceptibility to Infection in Liver
Cirrhosis
Norberto C. Chavez-Tapia, Aldo Torre-Delgadillo, Felix
I. Tellez Avila and Misael Uribe
There is much clinical evidence of a relationship between
infectious disease and chronic liver disease. The consequences
of this adverse association have been described and advances
in the treatment and prophylaxis of infectious disease have
had an important effect on the management of patients with
chronic liver disease. The association between infectious
disease and chronic liver disease involves altered cytokine
production, cellular immunity, and vascular response. However,
there is little information on the mechanisms underlying these
phenomena. In this report, we review the mechanistic basis
of this common association.
[Back to top]
Microtubule-Stabilizing Natural Products as Promising Cancer
Therapeutics
Brian M. Gallagher Jr.
Paclitaxel and related taxanes exhibit their anticancer
activity by promoting tubulin polymerization and stabilizing
microtu-bules, which results in mitotic G2/M arrest and apoptosis.
The clinical success of paclitaxel in treating a wide array
of tumor types has led to numerous efforts to identify novel
natural products with paclitaxel-like mechanisms of action,
but which may overcome some of the liabilities of the taxanes.
Although the list of natural products that share the paclitaxel-like
mechanism is relatively small, it continues to expand and
currently includes a number of structurally distinct classes.
Despite the mechanistic similarities between these classes,
differences exist which may translate into their differential
efficacy in the clinic. The past several years have seen a
considerable amount of pre-clinical and clinical progress
in developing these novel microtubule-stabilizing natural
products as cancer therapeutics. This review focuses primarily
on recent advances published since 2002.
[Back to top]
Oxidative RNA Damage and Neurodegeneration
A. Nunomura, P.I. Moreira, A. Takeda, M.A. Smith and G.
Perry
Although cellular RNA should be subject to the same oxidative
insults as DNA and other cellular macromolecules, oxidative
damage to RNA has not been a major focus in investigating
the magnitude and the biological consequences of the free
radical damage. However, because RNA is mostly single-stranded
and its bases are not protected by hydrogen bonding and are
less protected by specific proteins, RNA may be more susceptible
to oxidative insults than DNA. Thereafter, oxidative damage
to protein-coding RNA or non-coding RNA will potentially cause
errors in proteins or dysregulation of gene expression. While
less lethal than mutations in genome, such non-acutely lethal
insults to cells might be associated with underlying mechanisms
of several human diseases, especially chronic degeneration.
Recently, oxidative RNA damage has been described in several
neurodegenerative diseases including Alzheimer disease, Parkinson
disease, dementia with Lewy bodies, and prion diseases. Of
particular interest, oxidative RNA damage is a feature in
vulnerable neurons at the very earliest-stages of these diseases,
suggesting that RNA oxidation may actively contribute to the
onset or to the development of disease. Mechanistically speaking,
an increasing body of evidence suggests that the detrimental
effects of oxidative RNA damage to protein synthesis are attenuated,
at least in part, by the existence of mechanisms that avoid
the incorporation of the damaged ribonucleotides into the
translational machinery. Further investigations toward understanding
of the consequences and processing mechanisms related to oxidative
RNA damage may provide significant insights into the pathogenesis
and therapeutic strategies for neurode-generative and other
degenerative diseases.
[Back to top]
Towards the Development of a Broadly Protective Group A Streptococcal
Vaccine Based on the Lipid-Core Peptide System
C. Olive, P.M. Moyle and I. Toth
Preclinical studies carried out over the last seven years
by our group have focused on the development of a group A
strepto-coccal (GAS) vaccine based on the antiphagocytic bacterial
surface M protein using the Lipid-Core Peptide (LCP) system.
This synthetic peptide vaccine delivery system has several
advantages over other delivery systems including its self-adjuvanting
properties and the ability to incorporate multiple peptide
epitopes into a single vaccine. This review describes various
vaccine delivery strategies including the LCP system, highlighting
its functional properties and applications in vaccine research
using data obtained from various LCP-based GAS vaccine candidates
evaluated in murine models.
[Back to top]
Serotonin and Cognitive Flexibility: Neuroimaging Studies
into the Effect of Acute Tryptophan Depletion in Healthy Volunteers
E.A.T. Evers, F.M. van der Veen, D. Fekkes and J. Jolles
Cognitive flexibility is the ability to adjust behavior to
changes in the environment or task conditions. Previous research
sug-gested that serotonin (5-HT) is involved in cognitive
flexibility. Disturbed 5-HT functioning in animals, psychiatric
patients and healthy volunteers leads to more rigid behavior.
A well recognized method to manipulate levels of brain 5-HT
is acute tryptophan depletion (ATD). This method induces a
transient and reversible lowering of plasma tryptophan that
has been shown to result in decreased brain 5-HT. Only recently
has ATD research been combined with functional Magnetic Resonance
Imaging (fMRI). In this review, we discuss recent investigations
into the effect of ATD on the Blood Oxygen Level Dependent
(BOLD) response during tasks that require cognitive flexibility,
in healthy volunteers.
Functional MRI studies have shown that ATD changes brain activation
during tasks that require cognitive flexibility. It is hypothesized
that ATD changes the processing of negative feedback, rather
than impairing response inhibition, impairing the response
to an error or the loss of cognitive control during response
interference. Although the results of these studies are intriguing,
they are sometimes contradictory. This could be the result
of the different paradigms that have been used. Importantly,
these studies strongly suggest that future multidisciplinary
research should evaluate the mechanisms underlying individual
differences and control for variables that have been shown
to interact with the effect of ATD on cognitive flexibility
and the related brain activation.
[Back to top]
Recent Developments in Studies of l-Stepholidine
and its Analogs: Chemistry, Pharmacology and Clinical Implications
Jiao Mo, Yang Guo, Yu-She Yang, Jing-Shan Shen, Guo-Zhang
Jin and Xuechu Zhen
Tetrahydroprotoberberines (THPBs) represent a series
of compounds extracted from the Chinese herb Corydalis
ambigua and various species of Stephania. THPBs,
dependent on the presence of hydroxyl groups in its structure,
are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs
and dihydroxyl-THPBs. THPBs are identified as a new category
of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs
attracted particular attention because of their dual actions
on dopamine (DA) receptors. They exhibit D1
receptor agonistic activity while acting as D2
receptor antagonists. This unique pharmacological profile
made dihydroxy l-THPBs such as l-stepholidine
(l-SPD) potential agents in the treatment of drug
addiction, Parkinson’s disease, and especially, schizophrenia.
Clinical studies have shown that co-administration of l-SPD
with a typical antipsychotic drug significantly enhances the
therapeutic effects and remarkably reduces the tardive dyskinesia
induced by the typical antipsychotic drug used with schizophrenic
patients. Moreover, l-SPD alone was shown to have
therapeutic value without inducing significant extrapyramidal
side effects and also seemed to reduce the negative symptoms
of schizophrenia. This is confirmed in experimental studies
using animal models of schizophrenia, in which l-SPD
improved social interaction and cognitive function, inhibited
hyperactivity in schizophrenic animals. This review discusses
the chemistry, pharmacology and clinical implications of l-THPBs
in the drug development for psychosis and neurobiological
diseases.
[Back to top]
Predictive Models for hERG Channel Blockers: Ligand
Based and Structure-Based Approaches
Khac-Minh Thai and Gerhard F. Ecker
Acquired long QT syndrome caused by drugs that block
the human ether-a-go-go-related-gene (hERG) K+
channel causes se-vere side effects and thus represents a
major problem in clinical studies of drug candidates. Therefore,
early prediction of hERG K+
channel affinity of drug candidates is becoming increasingly
important in the drug discovery process. Both structure-based
and ligand-based approaches have been undertaken to shed more
light on the molecular basis of drug-channel interaction.
In this article, in silico approaches for prediction
of interaction with hERG are reviewed. Special attention is
drawn to the in vitro biological testing systems
as well as to consensus approaches for improvement of predictive
power.
[Back to top]
Calcium Sensing Receptor Activators: Calcimimetics
Paul E. Harrington and Christopher Fotsch
The calcium sensing receptor (CaR) is a G protein-coupled
receptor (GPCR) that plays a fundamental role in serum calcium
homeostasis. The CaR is expressed on the chief cells of the
parathyroid gland and is responsible for controlling the secretion
of parathyroid hormone (PTH). PTH acts on several organs including
the bone, kidney, and intestine to tightly regulate the concentration
of serum calcium. Substances other than calcium that activate
the CaR are referred to as calcimimetics. Calcimimetics that
bind to the CaR as agonists are referred to as type I. Type
II calcimimetics bind to a site that is distinct from the
physiological ligand and function as positive allosteric modulators
of the CaR. Type II calcimimetics amplify the sensitivity
of the CaR to serum calcium and are thus able to lower the
concentration of serum PTH. Calcimimetics are being pursued
as therapeutics for the treatment of disorders that are characterized
by elevated levels of PTH such as primary and secondary hyperparathyroidism
(primary HPT and secondary HPT). In this review, we provide
an overview of key results in the discovery of cinacalcet
HCl (Sensipar®
in the US, Mimpara®
in Europe). In addition, other recently disclosed type II
calcimimetics are discussed.
[Back to top]
Tamoxifen Resistance and Epigenetic Modifications in Breast
Cancer Cell Lines
Eric Badia, Joan Oliva, Patrick Balaguer and Vincent Cavaillès
Epigenetic mechanisms play crucial roles in many processes,
including neoplasia, genomic imprinting, gene silencing, differ-entiation,
embryogenesis and X chromosome inactivation. Their relevance
in human disease and therapy has grown rapidly with the recent
emergence of drugs that target for example DNA methylation
or histone acetylation. Epigenetic effects were also recently
highlighted by the deciphering of the mechanism of action
of steroid hormones and anti-hormones acting through nuclear
receptors. In this review, we focus on the epigenetic effects
associated with long-term treatment of breast cancer cells
with the antiestrogen (AE) tamoxifen, in the context of resistance
appearance. We summarize the data obtained with a model cell
line developed in our laboratory supporting a role for HP1
proteins in the irreversible inactivation of gene expression
by long-term treatment with AE.
[Back to top]
Regulation of Mast Cell Development by Inflammatory Factors
Zhi-Qing Hu, Wei-Hua Zhao and Tadakatsu Shimamura
Mast cells are potent effectors playing a key role in
IgE-associated hypersensitivity reactions, allergic disorders,
inflammation and protective immune responses. Mast cell development
in vivo occurs mainly in non-hematopoietic microenvironments
and increased mast cell numbers can be seen in various inflammatory
diseases and pathologic conditions. SCF (also known as kit
ligand or KitL) and c-kit signaling are essential
for both human and murine mast cell development, while IL-3
is required for murine mast cell hyperplasia that occurs in
response to various stimuli. Besides SCF and IL-3, the cytokines
IL-4, IL-9, IL-10 and IL-13 are also called mast cell growth
factors due to their actions synergistically promoting mast
cell proliferation and differentiation in the presence of
SCF or IL-3. These cytokines alone however are unable to support
neither the proliferation nor survival of mast cells. Most
research has focused on examining the direct effects of the
above cytokines on mast cells or their precursors. However,
it is difficult to explain the process of mast cell development
only in terms of the above mast cell growth factors. A series
of experiments in our laboratory and by others has revealed
that inflammatory mediators and cytokines, as triggers or
regulators, are also crucial for mast cell development. This
review summarizes recent progress in our understanding of
how various inflammatory factors regulate mast cell development,
with particular focus on the effects of prostaglandin E (PGE),
TNF-α ,
IL-6, IFN-γ
and an unknown apoptosis-inducing factor produced by IL-4-stimulated
macrophages.
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