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Medicinal Chemistry Reviews - Online, Volume 2, No. 3, 2005
Contents
A Review of Current Drug Targets and Pharmacology
of Antipsychotic Treatment
Pp.177-182
Robert
R. Conley and Deanna L. Kelly
Acquired Carbapenem-Hydrolyzing b-Lactamases and their Genetic Support - An
Update Pp.183-195
L.
Poirel and P. Nordmann
A Review of the Most Important Classes of
Serine Protease Inhibitors in Insects and Leeches Pp.197-206
E.
Clynen, L. Schoofs and M. Salzet
Recent Advances in the Industrial Enzymatic
Synthesis of Semi-Synthetic b-Lactam
Antibiotics Pp.207-218
Cesar
Mateo, Olga Abian, Valeria Grazu, Gloria Fernandez-Lorente, Jose M. Palomo,
Manuel Fuentes, Rosa L. Segura, Tamara Montes, Fernando Lopez-Gallego, Lorena
Wilson , Rodrigo Torres, Jose M. Guisan and Roberto Fernandez-Lafuente
Identification of Tumor Targeting Agents by
Phage Display Pp.219-229
Victor
I. Romanov
Leishmania-Host Interplay: The Everlasting
Rivalry Pp.231-249
A.
Martiny and M.A. Vannier-Santos
The Benzodiazepine Recognition Site on GABAA
Receptors Pp.251-256
Erwin
Sigel
Targeting DNA Associated Processes for Cancer
Therapy by the Use of SELEX and Anti-gene Approaches – When Selection Meets
Rational Design Pp.257-264
P.
Majumder, M. Faria and H. Ulrich
Abstracts
[Back to top] A Review of Current Drug Targets and
Pharmacology of Antipsychotic Treatment
With the use of
chlorpromazine and other traditional antipsychotics for psychosis, it was soon
discovered that the antipsychotic efficacy of this class of medications was
closely associated with their ability to block dopamine D2 receptors
in the brain. This prompted the hypothesis that the etiology of schizophrenia
and other psychotic illnesses might be caused by a dysregulation of dopamine.
This hypothesis, that the dopamine system explains schizophrenia symptoms,
however, is far from complete and the treatment with conventional antipsychotic
medications is far from ideal. There has been a great deal of speculation
regarding the role of serotonin receptor antagonism in regards to antipsychotic
effects. The second-generation antipsychotics (SGAs), clozapine, risperidone,
olanzapine, quetiapine, ziprasidone and aripiprazole generally have relatively
high serotonin to dopamine binding ratios. Serotonin receptor binding may be
important to these drugs’ actions, possibly by stimulating dopamine activity in
mesocortical pathways. Yet, while the mechanism of action of SGAs as a group
remain unsolved, it is important to note that the SGAs offer many clinical
benefits to treatment as compared to traditional antipsychotics and are quickly
emerging as first-line therapy for schizophrenia. In addition to lower rates of
EPS and tardive dyskinesia, other benefits to treatment with this class of
antipsychotics include better treatment of negative symptoms, better
compliance, possible benefits for cognitive impairments, lower rates of relapse
and rehospitalization, and more cost-effective therapy. Within the class of
SGAs, however, differences exist both in efficacy and side effects and these
will be described. Optimization of treatment and understanding the exact
mechanism of action of current antipsychotic medications will help pave the way
for new drug targets in the future.
[Back to top] Acquired Carbapenem-Hydrolyzing b-Lactamases and their Genetic Support - An
Update
L.
Poirel and P. Nordmann
Carbapenem-hydrolyzing
b-lactamases of several Ambler molecular
classes have been reported as the source of acquired b-lactam antibiotic resistance in Gram
negative bacteria. The metallo-enzymes of Ambler class B are the most prevalent
enzymes in this case. These clavulanic-acid resistant enzymes have a large
spectrum of hydrolysis including penicillins, cephalosporins (third and fourth
generations), carbapenems but not monobactams. They are responsible for
acquired resistance in several Gram negative species of clinical relevance in
human medicine. IMP-1 was the first reported as acquired in Japan, mostly from Serratia
marcescens and Pseudomonas aeruginosa isolates, and has been
detected in Europe recently. Several variants of IMP-1 (IMP-2 to -13) have been
characterized, possessing 85 to 99% amino acid identity, mostly from P.
aeruginosa isolates. In addition, VIM-1 to -7 b-lactamases have also been described, first
in Europe (Italy, France, and Greece) and now in Korea, Japan and also USA. The
VIM series shares 30% amino acid identity with the IMP-series. Most of these
class B enzymes have genes that are integron- and plasmid-located. Recently,
another class B enzyme, SPM-1, has been identified from P. aeruginosa isolates
in Brazil. This enzyme is weakly related to the others whereas sharing similar
biochemical properties. The common region CR4 transposable element is likely
involved in its acquisition. Finally, a few Ambler class A (SME-1, NMC-A,
IMI-1/-2, KPC-1/-2) and class D (OXA-23 to -27, OXA-40 and OXA-48) b-lactamases involved in carbapenem hydrolysis
have been reported also from rare Gram-negative isolates. This review
underlines the worldwide spread of carbapenem-hydrolyzing b-lactamases as
representing an important threat for efficacy of antibiotics in the near
future.
[Back to top] A
Review of the Most Important Classes of Serine Protease Inhibitors in Insects
and Leeches
E.
Clynen, L. Schoofs and M. Salzet
The constant
increase of life expectancy is associated with major aging of developed
populations. This indicates that the new century will have one of most epidemic
progressions of cardiovascular, cancer and inflammatory diseases. The high
challenge for medical research is to compress such morbidity. Invertebrates
have demonstrated to be truly useful models in drug discovery for such aging
diseases. The last decade, drug discovery in leeches has opened the gate for
new molecules to treat emphysema, coagulation, inflammation, dermatitis and
cancer. Also other invertebrates, such as insects, harvest potential
interesting molecules, such as serine protease inhibitors that can be exploited
by the medical industry. In this review we discuss the most important classes
of serine protease inhibitors in insects and leeches.
[Back to top] Recent Advances in the Industrial Enzymatic
Synthesis of Semi-Synthetic b-Lactam
Antibiotics
Cesar Mateo, Olga Abian, Valeria Grazu, Gloria Fernandez-Lorente, Jose M. Palomo, Manuel Fuentes, Rosa L. Segura, Tamara Montes, Fernando Lopez-Gallego, Lorena Wilson , Rodrigo Torres, Jose M. Guisan and Roberto Fernandez-Lafuente
The production,
under environmentally benign conditions, of efficient and more cost-effective
anti-infective agents (available to the whole mankind) is one of most ambitious
dreams of the industrial medicinal chemistry.
Semi-synthetic b-lactam antibiotics are very effective
anti-infective agents. They are very stable and can be used via oral delivery.
They exhibit a very wide spectrum of anti-bacterial activity and minimal side
effects after being massively used for a very long time. In this way, we can
assume that semi-synthetic b-lactam antibiotics are going to be one of
the key anti-infective agents in the next years.
The condensation
of natural or modified antibiotic nuclei with different acyl donor chains is
one of the key steps for the industrial synthesis of these anti-infective
agents. Up to now, these condensations are mainly carried out through classical
chemical methods and this implies a number of economical, ecological and
technological drawbacks (high energy requirements, many protection and
deprotection steps, utilization of toxic methylene chloride as solvent, etc).
Enzyme
biocatalysts may be very useful to catalyse these selective condensations under
very mild experimental and environmental conditions. In fact, the possibility of
using enzymes to carry out such biotransformations, at laboratory scale, has
been discussed and demonstrated a long time ago. However, industrial synthesis
of b-lactamic antibiotics is still carried out
via unfavorable chemical routes. In fact, enzymes have not been produced in the
nature to act in industrial reactors; so they are usually very unstable,
inhibited by substrates and products and they may not have ideal catalytic
properties for industrial uses (high reaction rates, required selectivity, ability
to reach quantitative synthetic yields, stable enough to run a number of
reaction cycles, etc). These limitations of enzyme biocatalysis become even
more significant mainly when the enzyme is going to be used with non-natural
substrates, catalysing non-natural processes and working under non-conventional
conditions.
However, in the
last ten years, a great number of papers have reported substantial improvement
of these enzymatic synthetic approaches (new enzymes, better enzyme
derivatives, improved reaction designs and so on) and it seems that a massive
industrial implementation of enzymes in antibiotic synthesis is approaching. In
this review, we would like to make a critical discussion of these very
interesting advances in the application of enzyme biocatalysts for the
industrial synthesis of semi-synthetic antibiotics.
[Back to top] Identification of Tumor Targeting Agents by
Phage Display
Victor
I. Romanov
Techniques of the
phage display libraries construction have been dramatically improved. This
allowed researchers to expand the application field to cancer biology. Tumor
targeting –selective delivery of active compounds to the tumor sites for cancer
imaging or treatment presents obvious advantages as compared to chemotherapeutic
approach-killing rapidly proliferating cells. Tumor-avid peptides can be
efficiently identified by means of phage display libraries.
The most direct
application of peptide-protein phage-displayed libraries is a selection of
ligands for individual molecules important for cancer development. This
includes identification of ligands for cell surface molecules, mapping
protein-protein interactions and delineation of signal transduction pathways.
Enzymes substrates and modulators of their activity can also be identified via
phage display-based selection. Recently, more complicated than individual
molecules, biological systems started to be used as targets for biopanning.
This includes combination of soluble proteins, cellular surfaces and even vasculature
or surface of whole organs. In addition, construction and application of cDNA
expression libraries in phage-based vectors recently received appreciation. The
use of the phage as a vector for targeted gene therapy is also considered. In
the current review, we will discuss the selection of tumor-targeting peptides
and proteins identified by means of random peptide and cDNA phage-displayed
libraries.
[Back to top] Leishmania-Host Interplay: The Everlasting Rivalry
A.
Martiny and M.A. Vannier-Santos
Parasitic protozoa
of the genus Leishmania infect mammalian mononuclear phagocytic cells
causing a potentially fatal disease with a broad spectrum of clinical
manifestations. The drugs of choice used in the leishmaniasis therapy are
significantly toxic, expensive and faced with a growing frequency of refractory
infections. Thus the search for new leishmanicidal compounds is urgently
required. In order to perform a proper drug design and to understand the modes
of action of such compounds it is necessary to elucidade the intrincate
cellular and molecular events that orchestrate the parasite biology. To invade
host cells Leishmania recruit different surface receptors that may
assist engaging the microbicidal responses. Even before gaining the
intracellular millieu these pathogens can deactivate and/or subvert the
phagocyte signal transduction machinery rendering these cells permissive to
infection. In the present review we attempted to approach some of the most
relevant cellular and biochemical invasion strategies employed by Leishmania
parasites.
[Back to top] The Benzodiazepine Recognition Site on GABAA
Receptors
Erwin
Sigel
Ligands of the benzodiazepine
binding site of the GABAA receptor come in three flavors: positive
allosteric modulators, negative allosteric modulators and antagonists all of
which can bind with high affinity. The GABAA receptor is a
pentameric protein which forms a chloride selective ion channel and ligands of
the benzodiazepine binding site stabilize three different conformations of this
protein. Classical benzodiazepines exert a positive allosteric effect by
increasing the apparent affinity of channel opening by the agonist
g-aminobutyric acid (GABA). We concentrate here on the major adult
isoform, the a1b2g2 GABAA receptor. The binding
pocket for benzodiazepines is located in a subunit cleft between a1 and g2
subunits in a position homologous to the agonist binding site for GABA
that is located between b2 and a1 subunits. It is reviewed here, how we
arrived at this picture. In particular, point mutations were performed in
combination with subsequent analysis of the expressed mutant proteins using
either electrophysiological techniques or radioactive ligand binding assays.
The predictive power of these methods is assessed by comparing the results with
the predictions that can be made on the basis of the recently published crystal
structure of the acetylcholine binding protein that shows homology to the
N-terminal, extracellular domain of the GABAA receptor.
[Back to top] Targeting DNA Associated Processes for Cancer
Therapy by the Use of SELEX and Anti-gene Approaches – When Selection Meets Rational
Design
P.
Majumder, M. Faria and H. Ulrich
In the multi-cause
and multi-step diseases we globally refer to as cancer, often the same or
redundant biochemical circuits are disrupted or uncoupled by the cumulative
action of diverse mutation events. Anticancer agents have been extensively
designed and selected by their ability to specifically interact with malignant
cells by the targeting of proteins, mRNAs or DNA sequences involved in the
production of a transformed phenotype. In the post-genomic age, the amount of
available information concerning DNA increases the interest of the genome and
associated proteins as drug targets. The SELEX (Systematic Evolution
of Ligands by EXponential enrichment) technique and Anti-gene
strategy are both based on the production of high affinity ligands targeted to
protein or nucleic acid counterparts, respectively. The different rational
backgrounds of SELEX and Anti-gene approaches might be the basis for a
complementary action in anti-cancer therapy.