Current Drug Targets – Infectious Disorders, Volume 2, No.3, 2002
Antiretroviral Therapy Regimens for
Neuro-AIDS Pp.187-192
G.
Arendt and H.J. von Giesen
Pandemic of Atopic Diseases – A Lack of
Microbial Exposure in Early Infancy? Pp.193-199
M.
Kalliomäki and E. Isolauri
Strategic Targeting of Essential
Host-pathogen Interactions in Chlamydial Disease Pp.201-216
B.K.
Coombes, D.L. Johnson and J.B. Mahony
Structure-Based Inhibitor Design Targeting
HIV-1 Integrase Pp.217-234
I.-J.
Chen, N. Neamati and A.D. MacKerell, Jr.
Histidine Kinase-mediated Signal Transduction
Systems of Pathogenic Microorganisms as Targets for Therapeutic Intervention Pp.235-246
K.
Stephenson and J.A. Hoch
The Role of the Cytoskeleton in the Life
Cycle of Viruses and Intracellular Bacteria: Tracks, Motors,and Polymerization
Machines Pp.247-264
E.L.
Bearer and P. Satpute-Krishnan
CCR5 Chemokine Receptors: Gatekeepers of
HIV-1 Infection Pp.265-278
W.
Kazmierski, L. Boone, W. Lawrence, C. Watson and T. Kenakin
[Back to top] Antiretroviral Therapy Regimens for
Neuro-AIDS
G. Arendt and H.J. von Giesen
In the era of
highly active antiretroviral therapy (HAART) the central nervous system (CNS)
becomes increasingly important as a sanctuary site for the human immunodeficiency
virus (HIV-1). HIV-1-associated brain disease is subdivided into the minor
cognitive/motor disorder, the minor cognitive/motor complex and the AIDS
dementia complex, all of which are predictive for patients´ deaths. CNS
effective therapy therefore influences the prognosis of each individual
patient. Thus, there is urgent need both for prophylactic and therapeutic
strategies preventing or treating HIV-1-associated CNS disease. HAART
consisting of two nucleoside analogues (NAs), one or two protease inhibitors
(PIs) and /or one non-nucleoside inhibitor of the reverse transcriptase (NNRTI)
has a neuroprophylactic value with regard to the manifestation of HIV-1
associated CNS disease. With regard to therapeutic effects, the NAs zidovudine
and stavudine penetrate into the cerebrospinal fluid and positively influence
HIV-1-associated brain disease. Adding a second NA has no additional
therapeutic effect. NNRTIs (nevirapine and efavirenz) are also CNS effective.
However, there is a subgroup of non-responders, who obviously need other forms
of therapeutic interventions. The very few existing studies point out that
patients with high plasma viral loads and neurological abnormalities should be
treated with a combination of two NAs and one NNRTI. The value of PIs for CNS
protection remains to be evaluated.
[Back to top] Pandemic of Atopic Diseases – A Lack of
Microbial Exposure in Early Infancy?
M.
Kalliomäki and E. Isolauri
Improved hygienic
conditions in Western societies have reduced early microbial exposure, which
has been proposed as a reason for the continuously rising prevalence of atopy
and subsequent atopic diseases: atopic eczema, allergic rhinitis and asthma
(The Hygiene Hypothesis of Allergy). This hypothesis is supported by
immunological data showing that the immune response to microbial antigens, both
pathogenic and non-pathogenic ones, is accompanied by preferential expression
of cytokines that counterbalance the T-helper 2-polarized cytokine production
of neonates, the continuity of which might lead to enhanced IgE production,
atopy, and atopic disease.Experimental, epidemiological and clinical studies,
conducted over the last decade, indicate that nonpathogenic microbes in the gut
might be a major factor essential for the maturation of the human immune system
to a nonatopic mode. A recent randomised, placebo-controlled trial demonstrated
that perinatal administration of probiotics, cultures of potentially beneficial
bacteria of the healthy gut microflora, halved the later development of atopic
eczema during the first two years of life.
Some putative
mechanisms of action of gut commensals in host-microbe interactions have been
described. Two structural components of bacteria, the lipopolysaccharide
portion of Gram-negative bacteria and specified CpG motif in bacterial DNA,
activate immunomodulatory genes via Toll-like receptors present e.g. on
intestinal epithelial cells thus controlling physiological cytokine milieu in
the gut. Probiotics have also been shown to reverse increased intestinal
permeability and to reduce antigen load in the gut by degrading and modifying
macromolecules. The actual preventive role of natural and genetically
constructed supplementary microbes in the development of immunological diseases,
like allergy, remains to be elucidated.
[Back to top] Strategic Targeting of Essential
Host-pathogen Interactions in Chlamydial Disease
B.K.
Coombes, D.L. Johnson and J.B. Mahony
The chlamydiae are
obligate intracellular gram-negative bacteria that are exquisitely adapted for
exploitation of their hosts and contribute to a wide range of acute and chronic
human diseases. Acute infections treated with non-cidal antibiotics can lead to
the development of persistent, non-replicating bacteria with the corollary that
these persistent (yet viable) chlamydiae can resist eradication by further
antimicrobial treatment and cause chronic disease. These findings highlight an
urgent need for therapeutics that are effective against persistent infections
and call for creative approaches to identify potential drug targets. The C.
pneumoniae and C. trachomatis genome projects have greatly expanded our
knowledge of chlamydial pathogenesis and have provided an enormous potential
for the identification and characterization of unknown genes and potential
virulence factors in these bacteria. As intracellular pathogens, chlamydiae
rely on host cells for all aspects of their survival, from the initial
attachment with host cell membranes, to cellular invasion, acquisition of host
cell metabolites and intracellular replication. As such, the molecules
participating in interactions with the host could be attractive targets for
therapeutic intervention. This review describes recent advances in chlamydial genomics,
proteomics and cell biology that have cast light on host-pathogen relations
that are essential for chlamydial survival. Using this knowledge, we discuss
how strategically interfering with essential interactions between chlamydiae
and the host cell could be exploited to develop an innovative, and potentially
more relevant arsenal of therapeutic compounds.
[Back to top] Structure-Based Inhibitor Design Targeting
HIV-1 Integrase
I.-J.
Chen, N. Neamati and A.D. MacKerell, Jr.
HIV integrase (IN)
is a viral-encoded protein that catalyzes the breaking and joining reactions
that mediate integration of viral DNA into the host genome. Therefore, IN
offers a unique target for the development of novel anti-HIV and anti-AIDS therapeutics.
To take advantage of this potential, drug discovery efforts via structurebased
design approaches have been undertaken. Presented is a review of computer-aided
drug design efforts targeting HIV IN. Included is an overview of the lifecycle
of HIV, with emphasis on the mechanism of action of IN, biological assays for
measuring IN activity and identifying IN inhibitors, and the appropriate
cell-based assays required for determining the antiviral activity of IN
inhibitors. This is followed by a review of the available three-dimensional
structures of HIV IN. Structure-based drug design efforts are then critiqued,
including both ligand-based (e.g. pharmacophore) and target-based (e.g.
docking) methods. Results from recent computational chemistry studies of IN are
also discussed.
[Back to
top] Histidine Kinase-mediated Signal Transduction
Systems of Pathogenic Microorganisms as Targets for Therapeutic Intervention
K. Stephenson and
J.A. Hoch
Pathogenic
bacteria must be able to sense and respond rapidly to signals emanating from
the host environment and use the signals to modulate the expression of genes
required for the infection process. Two-component signal transduction systems,
and their more complex variants known as phosphorelays, are woven within the
fabric of bacterial cellular regulatory processes and are used to regulate the
expression of genes involved in the virulence and antibiotic resistance
responses of a large number of pathogens of major public health concern.
The emergence of
strains of pathogenic bacteria that are resistant to multiple antibiotics has
driven the search for new targets and/or modes of action for anti-microbial
agents. The presence of essential two-component systems in bacteria and the
central role that these regulatory systems play in virulence and antibiotic
resistance has meant that two-component systems and phosphorelays have been
recognized as targets for antimicrobial intervention. This review will discuss
the role of these signal transduction pathways in virulence responses and
antibiotic sensitivity of pathogenic microorganisms and their potential use as
targets for antimicrobial therapy. In addition, the current status on the
development of inhibitors specific for two-component systems will be discussed.
[Back to top] The Role of the Cytoskeleton in the Life Cycle of Viruses and
Intracellular Bacteria: Tracks, Motors,and Polymerization Machines
E.L. Bearer and P. Satpute-Krishnan
Recent advances in
microbiology implicate the cytoskeleton in the life cycle of some pathogens,
such as intracellular bacteria, Rickettsia and viruses. The cellular
cytoskeleton provides the basis for intracellular movements such as those that
transport the pathogen to and from the cell surface to the nuclear region, or
those that produce cortical protrusions that project the pathogen outwards from
the cell surface towards an adjacent cell.
Transport in both
directions within the neuron is required for pathogens such as the herpesviruses
to travel to and from the nucleus and perinuclear region where replication
takes place. This trafficking is likely to depend on cellular motors moving on
a combination of microtubule and actin filament tracks. Recently, Bearer et al.
reconstituted retrograde transport of herpes simplex virus (HSV) in the giant
axon of the squid. These studies identified the tegument proteins as the viral
proteins most likely to recruit retrograde motors for the transport of HSV to
the neuronal nucleus. Similar microtubule-based intracellular movements are
part of the biological behavior of vaccinia, a poxvirus, and of adenovirus.
Pathogen-induced
surface projections and motility within the cortical cytoplasm also play a role
in the life cycle of intracellular pathogens. Such motility is driven by
pathogen-mediated actin polymerization. Virulence depends on this actin-based
motility, since virulence is reduced in Listeria ActA mutants that lack the
ability to recruit Arp2/3 and polymerize actin and in vaccinia virus mutants
that cannot stimulate actin polymerization.
Inhibition of
intracellular movements provides a potential strategy to limit pathogenicity.
The host cell motors and tracks, as well as the pathogen factors that interact
with them, are potential targets for novel antimicrobial therapy.
[Back to top] CCR5 Chemokine Receptors: Gatekeepers of HIV-1 Infection
W. Kazmierski, L. Boone, W. Lawrence, C. Watson and T. Kenakin
With the discovery
that CCR5 is the critical protein required for infection by M-tropic HIV, has
come huge research efforts, both in academia and industry, to try to exploit
this finding. Thus, research advances in the fields of virology, structural
protein chemistry, and receptor pharmacology have combined to add a new
understanding to the process of HIV fusion and possible mechanisms to prevent
HIV entry. This review will approach this field from a receptor pharmacology
viewpoint and outline some concepts of receptor allosterism and protein-protein
interaction which may be relevant to CCR5 blockade. Many of these ideas may be
explored in a practical sense with the advent of new small molecule CCR5
inhibitors currently entering the clinic.