| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 16, Number 34, 2009
Contents
Protein Cysteine Modifications: (2) Reactivity Specificity
and Topics of Medicinal Chemistry and Protein Engineering
Pp. 4490-4501
N. Nagahara, T. Matsumura, R. Okamoto and
Y. Kajihara
[Abstract] [Purchase
Article] [PMID:
19903155 PubMed - indexed for MEDLINE]
The Protein Therapy of Kallikrein in Cerebral Ischemic
Reperfusion Injury Pp. 4502-4510
Y. Tang, Y. Shao, J. Su, H. Zhou, L. Liu, H.
Ren and Q. Dong
[Abstract] [Purchase
Article]
Dietary n-3 PUFA Vascular Targeting and the Prevention
of Tumor Growth and Age-Related Macular Degeneration Pp.
4511-4526
S. Serini, E. Piccioni and G. Calviello
[Abstract] [Purchase
Article]
Expanding the Chemical Biologist's Tool
Kit: Chemical Labelling Strategies and Its Applications
Pp. 4527-4543
Souvik Chattopadhaya, Farhana B. Abu Bakar and
Shao Q. Yaox
[Abstract] [Purchase
Article]
The Drug Targeting and Delivery Approach Applied to
Pt-Antitumour Complexes. A Coordination Point of View
Pp. 4544-4580
E. Gabano, M. Ravera and D. Osella
[Abstract] [Purchase
Article]
Lymphatics and Inflammation Pp. 4581-4592
J. Wilting, J. Becker, K. Buttler and H.A. Weich
[Abstract] [Purchase
Article]
Hypoxia Inducible Factor 1 as a Therapeutic Target
in Ischemic Stroke Pp. 4593-4600
Honglian Shi
[Abstract] [Purchase
Article]
Quantification of Low-Density and High-Density Lipoproteins
in Human Serum by Material Enhanced Infrared Spectroscopy
(MEIRS) Pp. 4601-4608
C.H. Petter, N. Heigl, R. Bakry, G.K. Bonn, A. Ritsch
and C.W. Huck
[Abstract] [Purchase
Article]
Impairment of T Cell Immunity by the Respiratory Syncytial
Virus: Targeting Virulence Mechanisms for Therapy and Prophylaxis
Pp. 4609-4625
P.A. González, S.M. Bueno, C.A. Riedel and A.M.
Kalergis
[Abstract] [Purchase
Article]
Abstracts
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[PMID:
19903155 PubMed - indexed for MEDLINE]
Protein Cysteine Modifications: (2) Reactivity Specificity
and Topics of Medicinal Chemistry and Protein Engineering
N. Nagahara, T. Matsumura, R. Okamoto and
Y. Kajihara
Cysteine (cysteinyl residue) modifications in proteins result
in diversity in protein functions. The reaction specificity
of a protein with a modified cysteine residue is determined
by the overall conditions of the protein, including the spatial
position of the cysteine residue, electrostatic interactions
between cysteine residue and other charged residues, spatial
interactions between the cysteine residue and a chemical compound,
electrophilicity of the chemical compound, and the pH of the
solution. In cysteine-dependant enzymes, each specific type
of cysteine modification characterizes the catalytic mechanism
of the enzyme. Recently, the catalytic mechanisms of peroxiredoxins
and cysteine proteases, which contain a cysteine residue(s)
in their catalytic sites, have been elucidated. In the catalytic
process of peroxiredoxins, a sulfenyl intermediate is formed
by oxidation of the catalytic cysteine residue. On the other
hand, in cysteine proteases, the catalytic cysteine residue
reacts with the carboxyl carbon of a peptide substrate to
form an intermediate complex via S-alkylation. In this review,
we introduce the most current information on the applications
of cysteine thiol chemistry for in vitro glycoprotein synthesis.
Recently, a glycoprotein (monocyte chemotactic protein-3),
containing an intact human complex-type sialyloligosaccharide
has been chemically synthesized. The procedure used for this
could have applications in the development of new protein-based
drugs, including antineoplastic drugs and antibiotics. It
can also potentially be applied for improving the half-life
and reducing the toxicity of these drugs, and for preventing
the development of multidrug resistance.
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The Protein Therapy of Kallikrein in Cerebral Ischemic
Reperfusion Injury
Y. Tang, Y. Shao, J. Su, H. Zhou, L. Liu, H.
Ren and Q. Dong
Objective: Biomacromolecule like exogenous Kallikrein
is difficult to pass through biomembrane and blood brain barrier.
So, the use of exogenous Kallikrein for the therapy of nervous
system diseases is restricted. We constructed the Protein
Transduction Domain-Kallikrein (PTD-Kallikrein), checked its
function of penetration and biotoxicity, and observed its
influence on neurons and ischemic brain tissues.
Methods: PTD-Kallikrein (tissue kallikrein) was prepared
by chemical synthesis. After PTD-Kallikrein injected 2.5 hours,
rats brains were taken out and contents of Kallikrein were
quantitated to observe the function of passing through blood
brain barrier. Cell survival rate were measured by XTT methods
to determine the peptide’s biotoxicity. Apoptosis were
in-spected by TUNEL. PTD-Kallikrein was administrated immediately
after cerebral ischemia. 24h later, infarct volume was determined
by TTC stain and IL-1β,
TNF-α
as well as PGE2 were measured
by ELISA.
Results: 1. PTD-Kallikrein can pass through the biomembrane
and blood brain barrier; 2. PTD-Kallikrein itself has no obviously
biotoxicity. 3. PTD-Kallikrein increases cell survival rate,
decreases neurons apoptosis during OGD/recovery; 4. HOE140
inhibits the effects of PTD-Kallikrein. 5. PTD-Kallikrein
improves neurological impairment, decreases the infarct volume,
and inhibits the release of IL-1β,
TNF-α,
PGE2. 6. HOE140 inhibits
the effects of PTD-Kallikrein on ischemia-reperfusion injury.
Conclusions: 1. PTD-Kallikrein can pass through the
biomembrane and BBB efficiently and itself has no obviously
bio-toxicity. 2. PTD-Kallikrein has neuroprotective effect
on neurons and cerebral ischemia injury. 3. PTD-Kallikrein
is par-tially mediated by B2 receptors.
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Dietary n-3 PUFA Vascular Targeting and the Prevention
of Tumor Growth and Age-Related Macular Degeneration
S. Serini, E. Piccioni and G. Calviello
The protective role of dietary n-3 polyunsaturated fatty
acids (PUFAs) against cardiovascular diseases has been partly
related to their ability to modulate the risk condition known
as “endothelial dysfunction”, by reverting the
endothelial alterations associated to it (reduced vascular
reactivity, the proinflammatory state, and the prothrombotic
properties). Moreover, vasculature represents the target for
inhibition of pathologic neo-angiogenesis by n-3 PUFAs. This
effect is believed to contribute to the beneficial action
of these fatty acids against disorders which recognize neovascularization
as a crucial pathogenetic step for their development, such
as cancer and age-related macular degeneration (AMD). Many
epidemiological studies have been conducted to evaluate the
association between the intake of these fatty acids and the
risk of developing cancer or AMD, even though contrasting
and not definitive results have been obtained. Conversely,
plenty of preclinical and in vitro experimental studies
have provided evidence for the anti-angiogenic effects of
n-3 PUFAs, mainly studying neo-angiogenesis in general (using
normal endothelial cells in vitro) or as a step of
cancer growth. The main aim of this review is to critically
review the current evidence for the inhibition of the neo-angiogenic
process exerted by n-3 PUFAs in cancer and AMD, and to identify
possible molecular mechanisms that might contribute to their
beneficial effects.
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Expanding the Chemical Biologist's Tool Kit:
Chemical Labelling Strategies and Its Applications
Souvik Chattopadhaya, Farhana B. Abu Bakar and
Shao Q. Yaox
Methods that allow visualisation of proteins in living systems,
in real time have been key to our understanding of the molecular
underpinnings of life. Although the use of genetically encoded
fusions to fluorescent proteins have greatly advanced such
studies, the large size of these tags and their ability to
perturb protein activity have been major limitations. Attempts
to circumvent these issues have seen the genesis of complementary
strategies to chemically label/modify proteins. Chemical labelling
approaches seek to “decorate” biomolecules in
live cells through the site-specific introduction of a small,
non-native chemical tag (or reporter group). The introduced
tag is minimally invasive such that the activity and/or function
of the target molecule in not perturbed/compromised by its
inclusion. In most cases, this modification is brought about
by fusing target biomolecules to protein domains/ peptide
tags or via the incorporation of reactive “handles”
by either exploiting the cell’s biosynthetic machinery
or during protein synthesis. Selective tagging of the biomolecule
then proceeds via a bioorthogonal chemical reaction following
exogenous addition of probe(s). Depending on the nature of
the probe, the method can be applied to either visualise/track
the dynamics of target molecule(s) in their native cellular
milieu or for affinity enrichment for further downstream applications.
The versatility of these approaches has been demonstrated
by their ability to tag not just proteins but also intractable
biomolecules like glycans. In this review, we summarise the
various strategies available to “chemically” tag
protein, glycans and provide a comparative analysis their
advantages and disadvantages. We also highlight the many creative
applications of such methodologies and discuss their future
prospects.
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The Drug Targeting and Delivery Approach Applied to
Pt-Antitumour Complexes. A Coordination Point of View
E. Gabano, M. Ravera and D. Osella
Platinum-based anticancer chemotherapy is associated to severe
side effects because of its poor specificity. In particular,
the hydrolysis of Pt-based drugs generates cationic complexes
with electrophylic properties able to target DNA. The effectiveness
of this kind of chemotherapy relies solely on the proliferation
index of tumour cells, which is higher than in healthy cells.
In recent years, the “drug targeting and delivery”
approach has been developed in an attempt to reduce chemotherapy-related
systemic side effects by using vectors that selectively deliver
the cytotoxic agent to tumour cells, thus sparing healthy
cells. These vectors include bioactive substances, such as
nutrients, that more readily enter metabolically active tumour
cells, or hormones, folates and bile acids, that are selectively
conveyed by receptors/transporters often over-expressed in
cancer cells (active targeting). Alternatively, macromolecular
vectors, exploiting the so-called EPR (enhanced permeability
and retention) effect, can be used (passive targeting). The
bioactive or macromolecular vector must contain a coordinating
arm capable of binding the PtX2-unit,
acting either as carrier or leaving group for the cytotoxic
Pt-moiety. In both cases, the Pt-vector conjugate should be
promptly cleaved to generate the active species. The release
of platinum drugs from the pharmacophore is crucial for fine-tuning
of the overall cytotoxic properties of the conjugates. The
“drug targeting and delivery” method represents
an exciting field of research for improving the therapeutic
potential of the long established, very efficient, but intrinsically
non-specific Pt-based drugs.
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Lymphatics and Inflammation
J. Wilting, J. Becker, K. Buttler and H.A. Weich
Inflammation is a local or systemic tissue reaction caused
by external or internal stimuli with the objective to remove
the noxa, inhibit its further dissemination and eventually
repair damaged tissue. Blood vessels and perivascular connective
tissue are important regulators of the inflammatory process.
After a short initial ischemic phase, inflamed tissue is characterized
by hyperaemia and increased permeability of capillaries. Therefore,
blood vessels have been in the focus of inflammation research
for quite some time, whereas lymphatic vessels have been neglected.
Their reactivity is not immediately obvious, and, their identification
within the tissue has hardly been possible until lymphatic
endothelial cell (LEC)-specific molecules have been identified
a few years ago. This has opened up the possibility to study
lymphatics in normal and diseased tissues, and to isolate
LECs for transcriptome and proteome analyses. Initial studies
now provide evidence that lymphatics are not just a passive
route for circulating lymphocytes, but seem to be directly
involved in both the induction and the resolution of inflammation.
This review provides a summary on the basics of inflammation,
the structure of lymphatics and their molecular markers, human
inflammation-associated diseases and their relation to lymphatics,
animal models to study the interaction of lymphatics and inflammation,
and finally inflammation-associated molecules expressed in
LECs. The integration of lymphatics into inflammation research
opens up an exciting new field with great clinical potential.
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Hypoxia Inducible Factor 1 as a Therapeutic Target
in Ischemic Stroke
Honglian Shi
In stroke research, a significant focus is to develop therapeutic
strategies that prevent neuronal death and improve recovery.
Yet, few successful therapeutic strategies have emerged. Hypoxia-inducible
factor 1 (HIF-1) is a key regulator in hypoxia. It has been
suggested to be an important player in neurological outcomes
following ischemic stroke due to the functions of its downstream
genes. These include genes that promote glucose metabolism,
angiogenesis, erythropoiesis, and cell survival. Many lines
of evidence have shown that HIF-1 is induced in ischemic brains.
Importantly, it seems that HIF-1 is primarily induced in the
salvageable tissue of an ischemic brain, penumbra. However,
the effect of HIF-1 on neuronal tissue injuries is still debatable
based on evidence from in vitro and preclinical studies.
Furthermore, it is of im-portance to understand the mechanism
of HIF-1 degradation after its induction in ischemic brain.
This review provides a present understanding of the mechanism
of HIF-1 induction in ischemic neurons and the potential effect
of HIF-1 on ischemic brain tissue. The author also elaborates
on potential therapeutic approaches through understanding
of the induc-tion mechanism and of the potential role of HIF-1
in ischemic stroke.
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Quantification of Low-Density and High-Density Lipoproteins
in Human Serum by Material Enhanced Infrared Spectroscopy
(MEIRS)
C.H. Petter, N. Heigl, R. Bakry, G.K. Bonn, A. Ritsch
and C.W. Huck
A key risk factor in the development of atherosclerosis is
a high concentration of serum low density lipoprotein (LDL)-cholesterol.
The main purpose of this study was to assess the LDL and high
density lipoprotein (HDL) content in human serum by employing
near-infrared (NIR) spectroscopy and multivariate calibration
techniques. Initially a qualitative principal component analysis
(PCA) based cluster model was generated to evaluate the feasibility
of NIRS for classifying and identifying the LDL and HDL-cholesterol.
Therefore TiO2 beads were
used as an adsorbent for selectively im-mobilizing LDL and
HDL-cholesterol and further analysing the incubated and washed
samples via NIR diffuse reflection spectroscopy.
A principle component regression (PCR) model of 24 LDL standards
in a range from 500 – 3000 ppm (clinical value is 1500
ppm) and a partial least squares regression (PLSR) model of
25 HDL standards in a range from 100 – 1000 ppm (clinical
value is 400 ppm) were computed. Furthermore, the wavenumber
region between 4000 cm-1
and 7240 cm-1 was found comprising
the main spectral information regarding the TiO2-LDL
and TiO2-HDL composites.
The regression coefficients (r) for LDL and HDL were >
0.99 (calibration curve) and > 0.97 (validation curve),
respectively. The PCR model of TiO2-LDL
showed a standard error of estimation (SEE) of 122.80 ppm
and a standard error of prediction (SEP) of 121.15 ppm while
the PLSR model of TiO2-HDL
showed 47.70 and 47.14 ppm, respectively. In order to determine
the concentration of HDL in real serum samples, LDL was removed
by adding a precipitation reagent containing 10 mg/mL magnesium
dextran-sulfate, followed by incubation and centrifugation.
The pretreated serum samples were predicted by the PLSR model
while the standard deviation (SD) from the reference to the
NIR predicted values of six test samples in a concentration
range from 500 – 2500 ppm showed < 10 %.
These results indicate the usefulness of the NIR spectroscopy
(NIRS) as a potential alternative or even supplementary clinical
method for the quick determination of LDL and HDL in human
serum.
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Impairment of T Cell Immunity by the Respiratory Syncytial
Virus: Targeting Virulence Mechanisms for Therapy and Prophylaxis
P.A. González, S.M. Bueno, C.A. Riedel and A.M.
Kalergis
Worldwide, respiratory syncytial virus (RSV) causes severe
bronchiolitis and pneumonia in children, the elderly and immuno-compromised
individuals. Moreover, RSV is the mayor cause of infant hospitalization
due to lower respiratory infection, regardless socioeconomic
status. Accumulating data support the notion that immune responses
elicited against naturally acquired RSV infections are non-lasting
and inappropriate for efficient virus clearance. Although
there is consensus over the capacity of RSV to impair the
development of an effective and protective adaptive immune
response, very little is known about specific viral determinants
involved in these processes as well as the molecular mechanisms
de-veloped by this virus to inhibit T cell function. Recent
studies have provided evidence supporting an important role
for dendritic cells in RSV-induced suppression of immunity.
Although recognized for over 50 years as an important respiratory
pathogen and healthcare problem, to date there are no available
vaccines against this virus, which highlights the complexity
of RSV-induced immunopathology. The development of new prophylactic
and therapeutic tools against RSV requires the unveiling of
molecular mechanisms and virulence factors responsible for
the pathogenesis caused by this virus. In this review, we
discuss recent findings describing virulence mechanisms evolved
by RSV to negatively modulate the adaptive immune response
in the host. Furthermore, novel strategies aimed to induce
efficient T cell immunity against RSV are reviewed.
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