Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 3, No. 2, 2003
Contents
Biosynthetic Pathways of Plastid-Derived
Organelles as Potential Drug Targets Against Parasitic Apicomplexa Pp. 99-109
Frank
Seeber
AIDS-related Insulin Resistance and
Lipodystrophy Syndrome Pp.
111-117
Tomoshige
Kino and George P. Chrousos
Surface-Linked Liposomal Antigen Induces IgE
Selective Unresponsiveness in a T-Cell Independent Fashion Pp. 119-135
Tetsuya
Uchida
The Evolving Therapeutic Approaches for
Epstein-Barr Virus Infection in Immunocompetent and Immunocompromised
Individuals Pp. 137-142
Motohiko
Okano
Drug-Induced Aseptic Meningitis Pp. 143-149
Eustachio
Nettis , Gianfranco Calogiuri , Maria Cristina Colanardi , Antonio Ferrannini
and Alfredo Tursi
Metformin and its Liver Targets in the
Treatment of Type 2 Diabetes
Pp. 151-169
Jerry
Radziuk , Clifford J. Bailey , Nicolas F. Wiernsperger and John S. Yudkin
Abstracts
[Back to top] Biosynthetic Pathways of Plastid-Derived Organelles
as Potential Drug Targets Against Parasitic Apicomplexa
Frank
Seeber
Apicomplexan parasites
are a large phylum of unicellular and obligate intracellular organisms of great
medical importance. They include the human pathogens Plasmodium spp., the
causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of
immunosuppressed individuals and a common cause of congenital disease, together
affecting several hundred million people worldwide.
The search for new and
effective drugs against these pathogens has been boosted during the last years
by an unexpected finding. Through molecular and cell biological analysis it was
realized that probably most members of this phylum harbor a plastid-like
organelle, called the apicoplast, which probably is derived from the engulfment
of a red alga in ancient times. Although the apicoplast itself contains a small
circular genome, most of the proteome of this organelle is encoded in the
nuclear genome, and the proteins are subsequently transported to the
apicoplast. It is assumed to contain a number of unique metabolic pathways not
found in the vertebrate host, making it an ideal “playground” for those
interested in drug targets. Recent reports have shown that the rationale of
this approach is valid and that new drugs which are urgently needed especially
for plasmodial infections, might be developed in the near future based on these
targets. Amongst them are three enzymes of the plant-like fatty acid synthesis
machinery and enzymes of the non-mevalonat isoprenoid biosynthesis pathway.
From their presence in the apicoplast it can be concluded that fatty acid and
lipid biosynthesis seems to be a major function of the apicoplast. Another
recently described apicoplast enzyme, ferredoxin-NADP+-reductase and
its redox partner, ferredoxin, points to another interesting organelle-specific
biosynthetic pathway, namely [Fe-S] cluster biosynthesis. In the present
review, the fundamental aspects of the apicoplast as drug target will be
described, together with the specific pathways and their currently known
inhibitors. Furthermore, based on the recent findings potentially new targets
will be discussed. A short overview of the presently available high-throughput
methods for Apicomplexa to evaluate the potency of new inhibitory substances
will also be given.
[Back to top] AIDS-related Insulin Resistance and
Lipodystrophy Syndrome
Tomoshige
Kino and George P. Chrousos
The recent development
of highly active antiretroviral therapy (HAART) has drastically improved the
life expectancy of AIDS patients, by reducing infection-related mortality.
However, the prolongation of the lives of HIV-1-infected patients and/or the
long-term use of novel, potent antiviral agents have generated a score of new
problems and complications. Among them is the AIDS-related insulin resistance
and lipodystrophy syndrome, which is observed in 30-80% of AIDS patients who
are well controlled by HAART. This syndrome is associated with severe metabolic
disturbances, such as carbohydrate intolerance/diabetes mellitus and
dyslipidemia, which cause atherosclerotic cardiovascular disease. The etiology
of this syndrome appears to be multi-factorial; other than the anti-viral drugs,
hypercytokinemia and the HIV-1 infection itself, including the virally encoded
molecules Vpr and Tat, could contribute to the development of these pathologic
changes or increase the vulnerability of patients to the adverse effect of the
therapeutic compounds. In this article, we review our current understanding of
the pathogenesis and therapeutic approach of this newly emerging
AIDS-associated metabolic syndrome.
[Back to top] Surface-Linked Liposomal Antigen Induces IgE Selective
Unresponsiveness in a T-Cell Independent Fashion
Tetsuya
Uchida
We previously reported
that surface-linked liposomal antigen induced IgEselective unresponsiveness.
The results were consistent even when different coupling procedures for antigen
with liposomes, or for liposomes with different lipid components, were
employed. During the course of an investigation intended to clarify the
mechanism of IgE-selective unresponsiveness induced by surface-coupled
liposomal antigens, we discovered an alternative approach to regulate the
production of IgE, one that is independent of the activity of T-cells.
Immunization of mice with OVA-liposome conjugates induced IgE- selective
unresponsiveness without apparent Th1 polarization. Neither interleukin-12 (IL-12),
IL-10, nor CD8+ T-cells participated in the regulation. Further, CD4+
T-cells of mice immunized with OVA-liposome were capable of inducing
antigen-specific IgE synthesis in athymic nude mice immunized with
alum-adsorbed OVA. On the other hand, immunization of the recipient mice with
OVAliposome did not induce anti-OVA IgE production, even when CD4+
T-cells of mice immunized with alumadsorbed OVA were transferred. In the
secondary immune response, OVA-liposome enhanced anti-OVA IgG antibody
production but not the ongoing IgE production, suggesting that the
IgE-selective unresponsiveness induced by the liposomal antigen involved direct
effects on IgE but not IgG switching in vivo. These results suggest the role of
an alternative mechanism, one not involving T-cells, in the regulation of IgE
synthesis, and raise the possibility that surface-linked liposomal antigen is
potentially applicable for the development of a novel vaccine that induces the
least IgE synthesis. Moreover, given the relatively low allergic response to
and increased antigenicity of the allergen, this form of antigen preparation
would be applicable to allergen immunotherapy.
[Back to top] The Evolving Therapeutic Approaches for
Epstein-Barr Virus Infection in Immunocompetent and Immunocompromised
Individuals
Motohiko
Okano
Epstein-Barr virus
(EBV) is one of eight known human herpesviruses (HHVs). A primary EBV infection
is generally subclinical in immunocompetent individuals, but often causes
infectious mononucleosis (IM) in adolescents and adults, which is generally a
benign and self-limiting disease. Therefore, in immunocompetent individuals
only symptomatic treatment is recommended, although fatal or malignant diseases
such as fatal IM, Burkitt’s lymphoma (BL) and nasopharyngeal carcinoma (NPC)
may develop without obvious preceding immunodeficiency. However, in certain
circum stances such as in patients with hereditary immunodeficiencies, in
recipients receiving a potent immunosuppressant or in patients with acquired
immunodeficiency syndrome (AIDS), this virus strongly links to the development
of lethal lymphoproliferative diseases (LPD). These LPD range from IM-like
illness associated with polyclonal proliferation to malignant lymphoma in
monoclonal fashion. To date, no specific therapy has been available for latent
EBV infection itself, but understanding the underlying pathogenetic mechanisms
in each condition provides the possible treatment including anti-viral agents,
immune modulators and chemotherapeutic drugs. Furthermore, severe combined
immunodeficiency (SCID) mouse engrafted with human peripheral blood mononuclear
cells is a suitable model for EBV-associated LPD which occur in human beings.
Using this, several therapeutic trials have been investigated, and some are
possibly beneficial.
This concise review
focuses on recent understanding of the pathogenetic mechanisms in various
EBVassociated diseases in immunocompetent and immunocompromised individuals,
and discusses potent therapeutic approaches in each condition.
[Back to top] Drug-Induced Aseptic Meningitis
Eustachio
Nettis , Gianfranco Calogiuri , Maria Cristina Colanardi , Antonio Ferrannini
and Alfredo Tursi
Aseptic meningitis is a
rare but well-recognized complication of drug therapy. The clinical
presentation of drug-induced aseptic meningitis (DIAM) is distinct. Symptoms
typically include fever, neck stiffness, headache, confusion, nausea and
vomiting.
The major categories
of causative agents are non-steroidal anti-inflammatory drugs, antimicrobials
and also intravenous immunoglobulins, monoclonal antibodies and vaccines.
These drugs most
commonly implicated as causes of aseptic meningitis act more likely through an
immunological mechanisms. However, the exact pathogenetic mechanism of DIAM is
still unknown. The diagnosis of drug-induced aseptic meningitis is difficult
and infectious etiologies must be excluded. In some cases the diagnosis has
been confirmed by rechallenging the patient with the suspected agent. In this
case, informed written consent is necessary and rechallenge must be medically
supervised both to document the response and to offer medical care and advice,
if required. The outcome of DIAM is generally good, usually without long term
sequelae.
[Back to top] Metformin and its Liver Targets in the
Treatment of Type 2 Diabetes
Jerry Radziuk , Clifford J. Bailey , Nicolas F. Wiernsperger and John S. Yudkin
Although a number of
assessments disagree, the preponderance of the evidence indicates that the
major therapeutic action of metformin in type 2 diabetes (DM2) is on the liver,
and glucose production (EGP) in particular. At the level of this organ, the
actions of metformin can be characterized as pleiotropic. The major questions
addressed here are therefore: (i) the methodological aspects of the
determination of glucose fluxes: when glucose production is not found to be
elevated in type 2 diabetes, it is not surprising that little action of
metformin on this flux is found. The issues of populations examined,
experimental protocols, and quantitative methods of flux determination are
important in answering this question. Early morning EGP is increased and
constitutes a valid target for metformin. (ii) the multiple targets of
metformin: metformin acts at a number of sites and interacts with metabolites
and hormones. Some of these actions may be expressed at different doses.
Although their net effect is therapeutic, not all are oriented towards lowering
hyperglycemia, perhaps explaining the more modest effect of this drug than
could be anticipated from individual actions. Sites of metformin action can
therefore be considered as a compilation of valid therapeutic targets in DM2.
Gluconeogenesis, glycogenolysis and glycogen synthesis can be altered by
metformin, although in vivo, this also depends on the methodology. Component
processes from substrate supply and liver uptake, through a number of
glucogenic enzymes, as well as glycogen synthase and phosphorylase have all
been shown to be affected. (iii) unifying concepts: reported actions of
metformin on the mitochondrial respiratory chain, free fatty acid metabolism,
AMP-activated protein kinase, and on membrane proteins directly may all explain
subsets of actions that are seen, providing more integrated targets for
consideration in the therapy of DM2.