Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 3, Issue 2, 2003

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.

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.

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.

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.

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.

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.