Current Drug Targets - Infectious Disorders - Volume 1, Issue 2, 2001

DNA oligonucleotides as anti-HIV therapeutic agents have been developed for more than a decade. Numbers of oligonucleotides have been designed as potential anti-HIV inhibitors. Here we summarized the designed anti-viral oligonucletides in last decade and divided the designed DNA HIV inhibitors into three categories: (i) antisense inhibitors, (ii) triplex inhibitors and (iii) G-quartet inhibitors, based upon their inhibitory mechanism and structures. Also we proposed a strategy of rational drug design of anti-HIV oligonucleotides, which includes several critical steps, such as (1) structure-based rational drug design, (2) chemical synthesis / combinational chemistry, (3) the determination of structural properties, (4) assays of the inhibition of HIV-1 IN and virus replication, and (5) 3D QSAR operation. This methodology has been used by the design of G-quartet inhibitors.

Lipopolysaccharide (LPS) constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, and is essential for growth. LPS is also known to be responsible for the variety of biological effects associated with Gram-negative sepsis. In recent years, tremendous progress has been made in determining the exact chemical structure of this highly complex macromolecule, and recent advances have elucidated much of the enzymology involved in its biosynthesis. Using this knowledge, a number of inhibitors to LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. This review summarizes the main features of LPS structure, function, and biosynthesis, highlighting the potential target reactions that have been or might be exploited for therapeutic intervention.

To date, all approved drugs for the treatment of infection by human immunodeficiency virus type 1 (HIV-1) target either of two viral enzymes, reverse transcriptase or protease. Drugs targeting different macromolecules could improve upon current shortcomings (ex, drug resistance, metabolism, toxicity, formulation) and provide foundations for novel combination therapies. This review will focus on the two key challenges for any new target - target validation (demonstrating the role in the disease), and target tractability (the likelihood of identifying modulators of that target that have drug-like properties). For this discussion, drug-like molecules are orally active, relatively small organic molecules. All of the virally-encoded proteins (other than reverse transcriptase and protease) and the host targets that have been postulated to be critical for HIV-1 proliferation will be reviewed.

The bacterial ribosome is a target for a variety of drug classes including macrolides. Macrolide antibiotics are primarily used for the treatment of respiratory tract infections. One of the most important features of the macrolide class is the excellent safety profile allowing the drug to be used broadly across all age groups. The emergence of macrolide resistance, especially in S. pneumoniae, threatens the long-term usefulness of macrolide antibiotics. The newly developed ketolide class, including telithromycin and ABT-773, evolved from the macrolide class and displays significant improvements over macrolides while maintaining safety profiles similar to macrolides. The key improvement in antimicrobial spectrum is the in vitro potency against macrolide resistant pathogens, especially S. pneumoniae. This review outlines the key improvements of ketolides over macrolides in terms of in vitro microbiology, as well as the pharmacokinetic and pharmacodynamic profiles and updates the current understanding of drug-ribosome interactions. The application of cutting-edge technology such as ribosome structure-based rational drug design and genetic engineering are also briefly discussed.

Since the discovery of the human immunodeficiency virus type 1 (HIV-1) as the causative agent of AIDS in the early eighties, its spread has been dramatic. Current therapeutic strategies for the inhibition of viral replication employ a combination of drugs targeted at the viral reverse transcriptase and protease enzymes. The clinical benefit of this combination therapy is considerable, although often only transient, partly due to the emergence of multiple drug-resistant viral strains. The addition of new anti-HIV drugs targeting a third step of the viral replication may help in preventing resistance development. During HIV replication, the integration of the genome into the cellular chromosome is a vital step, which is catalysed by the viral integrase. The search for antiviral compounds capable of selective inhibition of integrase during viral replication is laborious and the large-scale screening programs for integrase inhibitors have thus far led to only one series of compounds that selectively inhibit the integration step of HIV replication, the diketo acids. In this review we summarize the current knowledge about HIV-1 integrase and integrase inhibitors. We address the issue why it is so difficult to find potent and selective integrase inhibitors, suitable to be included in a therapeutic drug combination and we propose new strategies for the discovery of integration inhibitors.

The human cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease for some time. The development of vascular disease involves a chronic inflammatory process with many contributing factors, and of these, chemokines and their receptors have recently been identified as key mediators. Interestingly, HCMV encodes four potential chemokine receptors (US27, US28, UL33 and UL78). Of these virally-encoded chemokine receptors, US28 has been the most widely characterized. US28 binds many of the CC-chemokines, and this class of chemokines contributes to the development of vascular disease. Importantly, HCMV infection mediates in vitro SMC migration, which is dependent upon expression of US28 and CC-chemokine binding. US28 and the US28 functional homologues that are capable of inducing the migration of SMC represent potential targets in the treatment of CMV-accelerated vascular disease such as atherosclerosis, restenosis, and transplant vascular sclerosis

1,3-beta-glucan synthase, a multisubunit enzyme, is responsible for fungal cell wall construction, division septum deposition, and ascospore wall assembly. The catalytic subunit of this enzyme complex, an integral membrane protein, has been identified both in model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and in pathogenic fungi such as Candida, Aspergillus, Cryptococcus and Pneumocystis species. The catalytic activity of the 1,3-beta-glucan synthase is regulated by a small GTPase of the Ras superfamily, the Rho-GTPase, and protein kinase C (Pkc)-like signaling molecules. It has been shown that the plasma membrane localization of this enzyme is essential for its activity. Interestingly, inhibition of 1,3-beta-glucan synthase activity by anti-fungal drugs of the lipopeptide type triggers a cell cycle feedback mechanism leading to cell cycle arrest. Recent progress in studies of molecular mechanisms of the temporal and spatial regulation of 1,3-beta-glucan synthase is presented. The implication of the cell cycle checkpoint that is activated by the anti-fungal drugs is also discussed.

Borrelia burgdorferi (sensu lato), the spirochete that causes Lyme disease, is among the most fascinating and enigmatic of bacterial pathogens. An obligate parasite of other organisms, B. burgdorferi is maintained in the mammalian reservoir (small rodents) by tick-mediated transmission from infected individuals to other members of the population. The complex requirements that must be met to ensure survival in an immunocompetent rodent and in the tick vector, coupled with a relatively small genome, suggest that B. burgdorferi has evolved elegant strategies for interacting with its hosts. Among these strategies are several distinct mechanisms of adhesion to mammalian cells and extracellular matrix components. The mammalian receptors for B. burgdorferi that have been most thoroughly studied, and for which candidate bacterial ligands have been identified, are decorin, fibronectin, glycosaminoglycans, and beta3-chain integrins.

The emergence of new antibiotic-resistance in the significant Gram-positive pathogens in the last decade created a substantial medical need for new classes of antibacterial agents. Pharmacia Corporation scientists initiated a discovery research program in oxazolidinone chemistry and biology. Indanone-, tetralone-, and indoline-subunit oxazolidinones provided proof-of-concept interim improvements in antibacterial activity and safety SAR for the program. A method for enantiomeric enrichment of analogs was developed and intensive synthesis and evaluation efforts were undertaken with three oxazolidinone subclasses; the piperazine, indoline, and tropones. Members of the piperazinyl-phenyloxazolidinones possessed the most suitable chemical characteristics and biologic activity of the three subclasses. The monofluorophenyl congener eperezolid and the morpholino analog linezolid emerged as the first clinical candidates from the piperazine oxazolidinones. Linezolid was selected for continued human clinical evaluation based upon its superior pharmacokinetic profile. Microbiologic testing revealed that linezolid compared very favorably against comparator antibiotics in vitro and in animal infection models. Linezolid possessed a unique mechanism of action in that it inhibited functional 70S initiation complex formation and did not cross-react with existing bacterial resistance. Oral bioavailability in humans was determined to be 100percent and twice daily dosing in humans resulted in blood levels which even at trough values were in excess of the MIC90 for significant Gram-positive pathogens. The preclinical promise of linezolid was realized in human clinical trials where linezolid was highly efficacious in the treatment of medically significant Gram-positive infections.

MurG is an essential bacterial glycosyltransferase that is involved in the biosynthesis of peptidoglycan. The enzyme is found in all organisms that synthesize peptidoglycan and is a target for the design of new antibiotics. A direct assay to study MurG was reported recently, followed shortly by the crystal structure of E. coli MurG. This first MurG structure, combined with sequence data on other glycosyltransferases, has revealed that MurG is a paradigm for a large family of metal ion-independent glycosyltransferases found in both eukaryotes and prokaryotes. A better understanding of MurG could lead to the development of new drugs to combat antibiotic resistant infections, and may also shed light on a broad class of glycosyltransferases.

Streptogramins A and B are chemically unrelated antimicrobials which act synergistically. This synergy is responsible for enhanced activity of the combination compared to each of the components and allows to overcome certain mechanisms of resistance to streptogramins B.. Although not completely elucidated, the mechanism of synergy is unique and based on a stable ribosome conformational change provoked by the binding of streptogramins A which unmasks a high affinity binding site for strepto- gramins B. A variety of resistance mechanisms to the A or B components by drug inactivation, target site modification, and active efflux have been reported. Acquired resistance to streptogramins A partially alters the synergy between the streptogramins A and B confirming the role of this component in the synergy. Full resistance in clinical isolates is due to combinations of genes for resistance to both components often associated on a single plasmid. Recently, a mutation in the L22 ribosomal protein of Staphylococcus aureus was found to confer resistance to streptogramins B and to abolish the synergy between A and B, probably by perturbing the association of this protein with 23S rRNA.

The most common cause of hepatic fibrosis is currently chronic HCV infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also regarded as the primary target cells for inflammatory stimuli, and produce extracellular matrix components. It should be noted that transforming growth factor beta (TGF-beta) is a potent fibrogenic cytokine produced by Kupffer cells and HSCs. There are several approaches to inhibit TGF-beta use of decorin, soluble receptors, and gene therapy approaches. Hepatocyte growth factor (HGF) is a hepatotrophic factor for liver regeneration and seems to suppress hepatic fibrogenesis in animals. HOE 77, Safironil, and S 4682 are inhibitors of prolyl 4-hydroxylase, which is essential for thecollagen formation. Although HOE 77, Safironil, and S 4682 seem to work by inhibiting HSC activation, further studies will be required before their clinical application. alpha-Tocopherol, retinyl palmitate, and silybinin reduce lipid peroxidation and attenuate HSC activation in experimental models. Retinyl palmitate is the main storage type for retinoids in HSCs. Silymarin is extracted from milk thistle, the principle component of which is the silybinin. Unfortunately, they have had mixed effects in human liver diseases. A Japanese herbal medicine Sho-saiko-to functions as a potent antifibrosuppressant via the inhibition of oxidative stress in hepatocytes and HSCs. Its active components are baicalin and baicalein of flavonoids with chemical structures very similar to silybinin. Understanding the basic mechanisms underlying the HCV-mediated fibrogenesis provides valuable information on the search for effective antifibrogenic therapies.