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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 23, 2006
Contents
Engineered T Cell Receptors and their Potential in Molecular
Medicine Pp. 2725-2736
John J. Miles, Sharon L. Silins and Scott R. Burrows
[Abstract]
Growth Factors and Chemokines: A Comparative
Functional Approach Between Invertebrates and Vertebrates
Pp. 2737-2750
G. Tettamanti, D. Malagoli, R. Benelli, A. Albini, A. Grimaldi,
G. Perletti, D.M. Noonan, M. de Eguileor and E. Ottaviani
[Abstract]
CRF Receptor Antagonists: Utility in Research
and Clinical Practice Pp. 2751-2760
E. Chatzaki, V. Minas, E. Zoumakis and A. Makrigiannakis
[Abstract]
Current Progress in Non-Invasive Imaging of
Beta Cell Mass of the Endocrine Pancreas Pp. 2761-2773
Fabiola Souza, Matthew Freeby, Kristi Hultman, Norman Simpson,
Alan Herron,Piotr Witkowsky, Eric Liu, Antonella Maffei and
Paul E. Harris
[Abstract]
Interaction Between Cytokines and Oxidative Stress
in Acute Pancreatitis Pp. 2775-2787
Javier Pereda, Luis Sabater, Luis Aparisi, Javier Escobar,
Juan Sandoval, José Viña, Gerardo López-Rodas
and Juan Sastre
[Abstract]
Tenofovir Plus Didanosine as Nrti Backbone in
HIV-Infected Subjects Pp. 2789-2793
Marco Bongiovanni and Federica Tordato
[Abstract]
Recent Advances in Coumarins and 1-Azacoumarins
as Versatile Biodynamic Agents Pp. 2795-2818
Manohar V. Kulkarni, Geeta M. Kulkarni, Chao-Hsiung Lin and
Chung-Ming Sun
[Abstract]
Molecular Imaging of Matrix Metalloproteinases
In Vivo Using Small Molecule Inhibitors for SPECT
and PET Pp. 2819-2838
S. Wagner, H.-J. Breyholz, A. Faust, C. Höltke, B. Levkau,
O. Schober,M. Schäfers and K. Kopka
[Abstract]
Treating Chronic Hepatitis B: Today and Tomorrow
Pp. 2839-2855
G. Borgia and I. Gentile
[Abstract]
Abstracts
[Back to top]
Engineered T Cell Receptors and their Potential in
Molecular Medicine
John J. Miles, Sharon L. Silins and Scott R. Burrows
T cell receptors are among the most
specific biological structures found in nature and are therefore
excellent candidates for the molecular targeting of antigen.
It is becoming increasingly apparent that common sets of T
cell receptors are frequently used in humans to combat pathogen
and cancer derived threats. Given that many of these conserved
T cell receptors have high affinity for their target ligands,
there is potential to amass virtual banks of “off-the-shelf”
receptors for use in a wide range of immunotherapeutic strategies.
Additionally, such T cell receptors could become basic blueprints
for artificial enhancement through mutagenesis, thereby creating
an even better 3-dimensional fit for their cognate targets.
Indeed, preliminary approaches using both “natural”
and “supernatural” T cell receptors have shown
promise in treating autoimmunity and malignancy. This review
will discuss these studies and other approaches through which
T cell receptors can be exploited in immunodiagnostics, pathogen
control and gene therapy.
[Back to top]
Growth Factors and Chemokines:
A Comparative Functional Approach Between Invertebrates and
Vertebrates
G. Tettamanti, D. Malagoli, R. Benelli, A. Albini, A. Grimaldi,
G. Perletti, D.M. Noonan, M. de Eguileor and E. Ottaviani
Growth factors and cytokines control and coordinate
a broad spectrum of fundamental cellular functions, and are
evolutionarily conserved both in vertebrates and invertebrates.
In this review, we focus our attention on the functional phylogenetic
aspects of growth factors/cytokines like the Transforming
Growth Factor-β
(TGF-β),
the Connective Tissue Growth Factor (CTGF), and the Vascular
Endothelial Growth Factor (VEGF). We will also delve into
the activites of two chemokine families, interleukin (IL)-8
(or CXCL8) and CC chemokine ligand 2/monocyte chemoattractant
protein-1 (CCL2). These molecules have been selected for their
involvement in immune responses and wound healing processes,
where they mediate and finely regulate various regeneration
processes like angiogenesis or fibroplasia, not only in vertebrates,
but also in invertebrates.
[Back to top]
CRF Receptor Antagonists: Utility in
Research and Clinical Practice
E. Chatzaki, V. Minas, E. Zoumakis and
A. Makrigiannakis
CRF, CRF-related peptides and CRF receptors
constitute a complex physiological system which has a key
role in facilitating the adaptation of the organism to the
stressful stimuli of the environment. The behavioral, endocrine,
auto-nomic and immune branches of stress response are considered
to be under the coordinating effects of CRF and its related
peptides. The effects of these peptides are mediated through
two distinct receptors, types 1 and 2 CRF receptors (CRF1
and CRF2). The two receptors are encoded by separate
genes and belong to the G-coupled receptor superfamily. The
wide influence of the CRF system on physiological processes
in both brain and periphery, suggests the implication of the
respective peptides in the pathophysiology of numerous disorders
which involve dysregulated stress responses. The potential
use of CRF antagonists in such disorders is currently under
intense investigation. Furthermore, such compounds have been
invaluable in elucidating the physiology of the CRF system.
This review will focus on existing data on the structural
and pharmacological characteristics as well as the experimental
and potential clinical uses of non-peptide, small molecule
CRF antagonists.
[Back to top]
Current Progress in Non-Invasive
Imaging of Beta Cell Mass 2761 of the Endocrine Pancreas
Fabiola Souza, Matthew Freeby, Kristi Hultman, Norman Simpson,
Alan Herron,Piotr Witkowsky, Eric Liu, Antonella Maffei and
Paul E. Harris
The increasing incidence of diabetes
requires a better understanding of the pathogenesis of the
clinical disease. Studies in prevention and treatment have
been hampered by the single end-point of diagnosis of diabetes
and hyperglycemia. The common pathology in both type 1 and
type 2 diabetes is insufficient beta-cell mass to meet the
metabolic demand. Unfortunately, current diagnostic methods
rely on metabolic responses that do not accurately reflect
true beta-cell mass. Recent advances in beta-cell imaging
have utilized multiple modalities in experimental and clinical
settings. While no “gold-standard” exists to measure
beta-cell mass, modalities such as single photon emission
computed tomography, optical and fluorescent imaging, magnetic
resonance imaging, and positron emission tomography have been
used with mixed success. Many of the methods are limited by
the inability to translate to the clinical setting, poor discrimination
between the exocrine and endocrine pancreas, or a poor measurement
of beta-cell mass. However, promising new “neuro-functional
imaging” approaches have emerged as improved measures
of beta-cell mass. We review the current understanding of
the pathogenesis and evaluation of diabetes, as well as experimental
approaches to assessing beta-cell mass.
[Back to top]
Interaction Between Cytokines
and Oxidative Stress in Acute Pancreatitis
Javier Pereda, Luis Sabater, Luis Aparisi, Javier Escobar,
Juan Sandoval, José Viña, Gerardo López-Rodas
and Juan Sastre
Acute pancreatitis is an inflammation
initially localized in the pancreatic gland which may lead
to local and systemic complications. The development of severe
acute pancreatitis is mediated by pathophysiological mechanisms
involved in the systemic inflammatory response, cytokines
and oxidative stress being their components of major importance.
Nevertheless, it is still unknown why an episode of acute
pancreatitis remains mild or progresses to a severe form.
Activated leukocytes are the main source of cytokines. Interleukin
1β
and tumor necrosis factor alpha (TNF-α)
initiate and propagate almost all the consequences of the
systemic inflammatory response syndrome, leading to amplification
of the inflammatory response. It is noteworthy that the systemic
inflammatory response is restrained and the rate of mortality
decreased in acute pancreatitis when TNF-α
is blocked with specific antibodies or in knock-out mice deficient
in its receptors. A synergy between pro-inflammatory cytokines
and oxidative stress occurs in the development of the inflammatory
response in acute pancreatitis. Pro-inflammatory cytokines
and oxidative stress trigger common signal transduction pathways
that lead to amplification of the inflammatory cascade, mainly
through activation of mitogen-activated protein kinases (MAPK)
and nuclear factor kappaB (NF-κB).
Furthermore, pro-inflammatory cytokines, particularly TNF-α,
and oxidative stress promote each other generating a vicious
circle in acute pancreatitis. This cross-talk that arises
between pro-inflammatory cytokines and oxidative stress greatly
contributes to amplification of the uncontrolled inflammatory
cascade through MAPK and NF-κB.
[Back to top]
Tenofovir Plus Didanosine
as Nrti Backbone in HIV-Infected Subjects
Marco Bongiovanni and Federica Tordato
Nucleoside reverse transcriptase
inhibitors (NRTI) are essential components of highly active
antiretroviral treatment (HAART). Although several combinations
can be used as NRTI backbones, not all are associated with
good virological and/or immunological results. In particular,
some NRTI combinations should be avoided due to antagonism
(zidovudine plus stavudine) or to high rate of toxicity (didanosine
plus stavudine). Tenofovir (TDF) and didanosine (ddI) are
among the more often prescribed NRTI for their convenient
posology (one pill each per day), relatively high genetic
barrier for resistance, quite acceptable safety profile and
remarkable antiviral potency when such drugs have been used
as single drug or in combinations with other NRTIs. However,
antiretroviral regimens containing TDF and ddI have been associated
with a high rate of virological failure in HIV-infected naïve
patients due to possible drug-interactions. The virological
efficacy of this backbone in HIV-infected, HAART pre-treated
subjects, is still controversial. Aim of this review is to
assess the possible role that antiretroviral regimens containing
TDF and ddI can have in the treatment of HIV-positive subjects,
focusing on their plasmatic and/or intracellular interactions
to optimize the antiretroviral efficacy and minimize the toxicities
of this combination.
[Back to top]
Recent Advances in Coumarins
and 1-Azacoumarins as Versatile Biodynamic Agents
Manohar V. Kulkarni, Geeta M. Kulkarni, Chao-Hsiung Lin and
Chung-Ming Sun
Coumarins, also referred as benzopyran-2-ones,
and their corresponding nitrogen counterpart, 1-azacoumarins
also referred to as carbostyrils, are a family of nature-occurring
lactones and lactams respectively. The plant extracts containing
coumarin-related heterocycles, which were employed as herbal
remedies in early days, have now been extensively studied
for their biological activities. These investigations have
revealed their potentials as versatile biodynamic agents.
For example, coumarins with phenolic hydroxyl groups have
the ability to scavenge reactive oxygen species and thus prevent
the formation of 5-HETE and HHT in the arachidonic pathway
of inflammation suppression. Recent in vivo studies
have revealed the role of coumarins in hepatotoxicity and
also in depletion of cytochrome P450. Similarly 1-azacoumarins
which is part of quinoline alkaloids, are known for their
diverse biological activity and recently, a 6-functionalized
1-aza coumarins are undergoing human clinical trials as an
orally active anti-tumor drug in view of its farnesyl protein-inhibiting
activity in the nanomolar range. Furthermore, several synthetic
coumarins with a variety of pharmacophoric groups at C-3,
C-4 and C-7 positions have been intensively screened for anti-microbial,
anti-HIV, anti-cancer, lipid-lowering, anti-oxidant, and anti-coagulation
activities.
Specifically, coumarin-3-sulfonamides and carboxamides were
reported to exhibit selective cytotoxicity against mammalian
cancer cell lines. The C4-substituted aryloxymethyl, arylaminomethyl,
and dichloroacetamidomethyl coumarins, along with the corresponding
1-azacoumarins, have been demonstrated to be potential anti-microbial
and anti-inflammatory agents. To expand the structural diversity
of synthetic courmarins for biological functions, attempts
have also been made to attach a chloramphenicol side chain
at C-3 position of courmarin. In addition, the bi- and tri-heterocyclic
coumarins and 1-azacoumarins with benzofuran, furan and thiazole
ring systems along with biocompatible fragments like vanillin
have shown remarkable potency as anti-inflammatory agents
in animal models.
Photobiological studies on pyridine-fused polycyclic coumarins
have highlighted their potential as thymine dimer photosensitisers
and the structurally related compounds of both coumarin and
carbostyrils have also been found to act via the
DNA gyrase pathway in their anti-bacterial activity. Apart
from the above works, the present review also addresses the
potential roles of coumarins and carbostyrils as protease
inhibitors, or fluorescent probes in mechanistic investigation
of biochemical pathways, and their application for QSAR in
theoretical studies. Though 1-Azacoumarins have received less
attention as compared to coumarins in the literature, an attempt
has been made to compare both the systems at various stages,
so that it can spark new thoughts on synthetic methodologies,
reactivity pattern and biological activities.
[Back to top]
Molecular Imaging of Matrix
Metalloproteinases In Vivo Using Small Molecule Inhibitors
for SPECT and PET
S. Wagner, H.-J. Breyholz, A. Faust, C. Höltke, B. Levkau,
O. Schober,M. Schäfers and K. Kopka
Matrix metalloproteinases (MMPs)
are a family of zinc- and calcium-dependent secreted or membrane
anchored endopeptidases. MMPs are involved in many physiological
processes but also take part in the pathophysiological mechanisms
responsible for a wide range of diseases. Pathological expression
and activation of MMPs are associated with cancer, atherosclerosis,
stroke, arthritis, periodontal disease, multiple sclerosis
and liver fibrosis. Thus, noninvasive visualisation and quantification
of MMP activity in vivo are of great interest in
basic research and clinical application. This can be achieved
by scintigraphic molecular imaging techniques such as single
photon emission computed tomography (SPECT) and positron emission
tomography (PET) provided suitable radiolabelled tracers exist,
e.g. radioactive inhibitors of matrix metalloproteinases (MMPIs).
The approach to monitor MMP activity in vivo using
radiolabelled small molecule inhibitors suitable for SPECT
and PET is summarised in this review. Briefly, latest advances
in scintigraphic imaging are introduced and followed by a
report about the enzyme class of MMPs. The involvement of
MMPs in cancer and atherosclerosis is exemplified and small
molecule MMPIs are classified. Subsequently, the development
of radiolabelled small molecule MMPIs, their synthesis and
in vitro and in vivo evaluation is reviewed.
Finally, an outlook on the clinical potential of labelled
MMPIs in diagnostic algorithms is given.
[Back to top]
Treating Chronic Hepatitis
B: Today and Tomorrow
G. Borgia and I. Gentile
Three hundred and fifty million people
worldwide are estimated to be chronically infected with hepatitis
B virus. 15-40% of these subjects will develop cirrhosis,
liver failure or hepatocellular carcinoma during their life.
The treatment of chronic hepatitis B has improved dramatically
over the last decade thanks to the advent of nucleo-side/nucleotide
analogues and the use of pegylated interferons. However, these
agents have increased the complexity of the management of
hepatitis B. Five drugs have been approved for chronic hepatitis
B treatment: standard interferon-α
2b, pegylated interferon-α
2a, lamivudine, adefovir dipivoxil, and entecavir. A definite
course of standard or pegylated interferon is administered
to induce hepatitis B virus clearance. Unfortunately, these
agents are not effective in all patients and are associated
with not negligible side effects. Nucleoside or nucleotide
analogues that inhibit hepatitis B virus polymerase induce
on-treatment suppression of viral replication but patients
tend to relapse after cessation of treatment. Consequently,
these analogues, which are well tolerated, should be used
for prolonged periods, even indefinitely. However, prolonged
treatment is associated with a high rate of resistance. The
following anti-hepatitis B virus drugs are currently undergoing
clinical testing: telbivudine, emtricitabine, tenofovir disoproxil
fumarate, clevudine and thymosin-<1.
Here we will examine the mechanism of action, efficacy, safety,
tolerability and emergence of resistance of agents used to
treat chronic hepatitis B. We shall also examine the potential
of drugs now being tested and of combination treatment.
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