Current Drug Targets - Infectious Disorders, Volume 1, Number 2, 2001
Contents
Rational Drug Design of DNA Oligonucleotides as HIV Inhibitors Pp. 79-90
Lipopolysaccharide as a Target for the Development of Novel Therapeutics in Gram-Negative Bacteria Pp. 91-106
Unexploited Viral and Host Targets for the Treatment of Human Immunodeficiency Virus Type 1 Infection Pp. 107-123
The Emerging New Generation of Antibiotic: Ketolides Pp. 125-131
HIV-1 Integration as a Target for Antiretroviral Therapy: A Review Pp. 133-149
W. Pluymers,
E. De Clercq and Z. Debyser
The HCMV Chemokine Receptor US28 is a Potential Target in Vascular Disease Pp. 151-158
D. N.
Streblow, S. L. Orloff and J. A. Nelson
1,3-b-Glucan Synthase: A Useful Target for Antifungal Drugs Pp. 159-169
Adhesion Mechanisms of the Lyme Disease Spirochete, Borrelia burgdorferi Pp. 171-179
J. Coburn
The Discovery of Linezolid, the First Oxazolidinone Antibacterial Agent Pp. 181-199
C.W. Ford,
G.E. Zurenko and M.R. Barbachyn
E. Coli MurG: A Paradigm for a Superfamily of Glycosyltransferases Pp. 201-213
S. Ha, B.
Gross, and S. Walker,
Overcoming Bacterial Resistance by Dual Target Inhibition: The Case of Streptogramins Pp. 215-225
A.Canu1 and R.
Leclercq
Antifibrogenic Therapies in Chronic HCV Infection Pp. 227-240
I. Shimizu
[Back to top] Rational Drug Design of DNA Oligonucleotides as HIV Inhibitors
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.
[Back to top] Lipopolysaccharide as a Target for the Development of Novel Therapeutics in Gram-Negative Bacteria
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.
[Back to top] Unexploited Viral and Host Targets for the Treatment of Human Immunodeficiency Virus Type 1 Infection
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.
[Back to top] The Emerging New Generation of Antibiotic: Ketolides
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.
[Back to top] HIV-1 Integration as a Target for Antiretroviral Therapy: A Review
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.
[Back to top] The HCMV Chemokine Receptor US28 is a Potential Target in Vascular Disease
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.
[Back to top] 1,3-b-Glucan Synthase: A Useful Target for Antifungal Drugs
1,3-b-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-b-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-b-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-b-glucan synthase is presented. The implication of the cell cycle checkpoint that is activated by the anti-fungal drugs is also discussed.
[Back to top] Adhesion Mechanisms of the Lyme Disease Spirochete, Borrelia burgdorferi
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 b3-chain integrins.
[Back to top] The Discovery of Linezolid, the First Oxazolidinone Antibacterial Agent
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 100% 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.
[Back to top] E. Coli MurG: A Paradigm for a Superfamily of Glycosyltransferases
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.
[Back to top] Overcoming Bacterial Resistance by Dual Target Inhibition: The Case of Streptogramins
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.
[Back to top] Antifibrogenic Therapies in Chronic HCV Infection
Ichiro Shimizu
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 b (TGF-b) is a potent fibrogenic
cytokine produced by
Kupffer cells and HSCs. There are several approaches to inhibit TGF-b; 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. a-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.