Medicinal Chemistry Reviews - Online (Discontinued) - Volume 2, Issue 3, 2005

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.

Carbapenem-hydrolyzing β-lactamases of several Ambler molecular classes have been reported as the source of acquired β-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 β-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 Gramnegative 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.

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.

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 βlactam 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 β-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 βlactamic 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.

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 approachkilling 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 proteinprotein 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.

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.

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 γ-aminobutyric acid (GABA). We concentrate here on the major adult isoform, the α1β2γ2 GABAA receptor. The binding pocket for benzodiazepines is located in a subunit cleft between α1 and γ2 subunits in a position homologous to the agonist binding site for GABA that is located between β2 and α1 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.

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 anticancer therapy.