Current Medicinal Chemistry - Volume 14, Issue 12, 2007

Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.

The vitamin B6-derived pyridoxal 5'-phosphate (PLP) is the cofactor of enzymes catalyzing a large variety of chemical reactions mainly involved in amino acid metabolism. These enzymes have been divided in five families and fold types on the basis of evolutionary relationships and protein structural organization. Almost 1.5% of all genes in prokaryotes code for PLP-dependent enzymes, whereas the percentage is substantially lower in eukaryotes. Although about 4% of enzyme-catalyzed reactions catalogued by the Enzyme Commission are PLP-dependent, only a few enzymes are targets of approved drugs and about twenty are recognised as potential targets for drugs or herbicides. PLP-dependent enzymes for which there are already commercially available drugs are DOPA decarboxylase (involved in the Parkinson disease), GABA aminotransferase (epilepsy), serine hydroxymethyltransferase (tumors and malaria), ornithine decarboxylase (African sleeping sickness and, potentially, tumors), alanine racemase (antibacterial agents), and human cytosolic branched-chain aminotransferase (pathological states associated to the GABA/glutamate equilibrium concentrations). Within each family or metabolic pathway, the enzymes for which drugs have been already approved for clinical use are discussed first, reporting the enzyme structure, the catalytic mechanism, the mechanism of enzyme inactivation or modulation by substrate-like or transition state-like drugs, and on-going research for increasing specificity and decreasing side-effects. Then, PLP-dependent enzymes that have been recently characterized and proposed as drug targets are reported. Finally, the relevance of recent genomic analysis of PLP-dependent enzymes for the selection of drug targets is discussed.

The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-Δ32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX3CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.

Pulmonary delivery of insulin is more than a promise in the treatment of diabetes mellitus. Inhaled insulin seems at least as efficacious as the conventional regimen of subcutaneous insulin and/or oral glucose-lowering agents in both type 1 and type 2 diabetes mellitus. Improved metabolic control and the use of a non-invasive route of administration represent the main benefits of this new treatment. Several physico-chemical factors could reduce the bioavailability of inhaled insulin. Indeed, both deep-lung deposition and adsorption of insulin variously depend on the type of propellants used, speed of air flow, particle size and velocity, drug deposition into the throat and larger bronchial tree. These factors, in turn, depend on the pulmonary delivery systems used and on respiratory mechanics and flows. Furthermore, the pharmacokinetics of inhaled insulin is affected by smoke, which increases its absorption, and by lung diseases, which decrease the available alveolar-capillary surface. Selected abnormalities of respiratory function complicate both type 1 and type 2 diabetes mellitus and a mild depression of carbon monoxide lung transfer after a 6-month period of treatment with inhaled insulin has been reported. Finally, results from some longitudinal studies suggest that diabetes might speed up the age-related decline of lung volumes and probably alter the pharmacokinetics of inhaled insulin, particularly in the elderly. Clarifying these issues is mandatory in order to define the indications and safety of inhaled insulin.

Since the publication of the review by Li and Dias in 1997, which covered almost all steroid dimers known to us until the early part of 1997, there have been significant amounts of work carried out on steroid dimers, and another review on this topic has long been overdue. Thus, this review presents a comprehensive review of literature published over the last decade on various aspects of steroid dimers, including synthesis and applications. Steroid dimers that were published before 1997 but were not covered within the previous review have also been included.

Panax ginseng C.A. Meyer, one of the most popular and valued herbs, has been used extensively in traditional Chinese medicine for thousands of years. More than thirty ginsenosides, the pharmacologically active ingredients in ginseng, have been identified with various sugar moieties attached at the C-3, C-6 and C-20 positions of the steroidal skeleton. We herein review the current literature on the pharmacological effects of ginsenosides on the modulation of angiogenesis, dysregulations of which contribute towards many pathological conditions. Regarding the adaptogenic property of ginseng, the effects of ginsenosides on central nervous system are also discussed. Recent researches have pointed to the steroid hormone receptors as the target molecules to elicit the diverse cellular and physiological activities of ginseng. We believe that understanding the interaction between ginsenosides and various steroid hormone receptors may provide clues to unravel the secret of ginseng.