Current Medicinal Chemistry - Volume 14, Issue 26, 2007

The introduction of highly active antiretroviral therapy (HAART) in 1996 dramatically changed the course of HIV infection. This therapy involves the use of at least three agents from two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Nine drugs containing PIs are clinically available: the first generation ones, saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir, and the second generation ones, fosamprenavir (the amprenavir prodrug), lopinavir, atazanavir, and tipranavir. Many other compounds are in advanced clinical evaluation, such as among others TMC-114, whereas a lot of different other effective HIV protease inhibitors were reported, mainly by using amprenavir and TMC-114 as lead molecules. The main goals of research in this field are: (i) the design of better pharmacological agents, devoid of severe side effects, resistance problems and with simple administration schedules (preferably once daily), and (ii) achieving eradication of the virus, and possibly, a definitive cure of the disease. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to PI drugs may be managed better by taking them into account (such as for example ritonavir boosting of other PIs which reduces dosages and administration schedules of these drugs). Except for being highly effective in the treatment of HIV infection, recent reports showed this class of drugs to be effective as antitumor agents, as antibacterials (for example against Mycobacterium tuberculosis infection), antifungals (against Candida albicans), antimalarials, antiSARS and anti-influenza agents.

The renin-angiotensin system (RAS) is frequently activated in the patients with chronic liver diseases, and recent studies have shown that RAS plays a pivotal role in the progression of chronic liver diseases, i.e., liver fibrosis and hepatocellular carcinoma (HCC). Angiotensin-II (AT-II) reportedly stimulates contractility and proliferation of the activated hepatic stellate cells, and increases the transforming growth factor-β (TGF-β) expression through angiotensin type-I receptors (AT1-R). Many studies have demonstrated that the clinically used angiotensin-converting enzyme inhibitors (ACE-I) and AT1-R blockers (ARB) significantly attenuated the liver fibrosis development in the experimental studies and clinical practice. AT-II also strongly promotes neovascularization, which plays a pivotal role in tumor development. AT-II induces a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). It has been reported that ACE-I significantly attenuated the experimental HCC growth and hepatocarcinogenesis along with suppression of neovascularization. The VEGF expression in the tumor was suppressed by ACE-I, too. The combined treatment of ACE-I with other clinically used agents, such as interferon, imatinib mesylate, and vitamin K, shows more potent inhibitory effects on the development of liver fibrosis and HCC. Since RAS inhibitors are widely used in the clinical practice without serious side effects, they may represent a potential new therapeutic strategy against the progression of chronic liver diseases.

A successful unified pharmacophore/receptor model which has guided the synthesis of subtype selective compounds is reviewed in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with a comparative model of the α1β2γ2 GABAA receptor leads to an orientation of the pharmacophore model within the Bz BS. Results not only are important for the rational design of selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket.

Respiratory viral infections account for a substantial proportion of morbidity world wide and contribute notably to the socioeconomic burden of diseases. Amongst the most important viruses identified so far are Rhinoviruses, Influenza A and Respiratory Syncytial Virus. The knowledge base has broadened at the clinical and experimental level in recent years. However, therapeutic options are still limited. This may be partly due to the multiplicity of infectious mechanisms and the complex underlying host/virus interactions. The aim of this article is to give an overview of the different respiratory viruses involved, their major principles of infection and the associated therapeutic targets and to review up-to-date virus-specific clinical trials.

The diagnosis of pituitary disorders is difficult because several hormone systems are involved. The clinical presentation is often vague and slowly progressing, and clinicians therefore have to rely very much on correct biochemical measurements. This is also associated with difficulties since the pituitary hormones interact, the binding proteins are influenced by the other axes and a variety of other effects, and finally the hormone measurements in serum are not totally adequate Several studies have investigated the interaction between the thyroid and growth hormone axes with very variable results. The present review is focussing on the aspects related to clinical decision making based on biochemical assessments. Because of the strong and sometimes unpredictable interrelations between the hypothalamo-pituitary thyroid and the hypothalamo-GHIGF axes, and the many pitfalls in the measurement of peripheral hormones and interpretation of stimulation tests, clinicians and clinical biochemists should collaborate closely. Only then can the diagnostic accuracy and the management of patients with both growth hormone and thyroid disorders be improved.

Naturally occurring and synthetic peptides may be a novel class of clinically useful antibiotics. A large body of experimental data on structure function relationships for such peptides is available, but the molecular mechanism of their action remains elusive in most cases. Computer simulations can give detailed insights into the interactions between peptides and lipid bilayers, at least one crucial step in the antimicrobial mechanism. Here we review recent simulations of antimicrobial peptides and discuss potential future contributions of computer simulations in understanding and ultimately designing antimicrobial peptides.

Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

The O-N intramolecular acyl migration, also named as an acyl shift or acyl transfer reaction, is well-known in organic and peptide chemistry as a simple rearrangement which proceeds under very mild aqueous conditions. Despite a long history with this reaction, its application in medicinal chemistry has only lately been proposed. In the last decade, this reaction has been intensively studied and several applications of this rearrangement in medicinal chemistry have appeared. O-N Intramolecular acyl migration has been employed in “no auxiliary, no byproduct” prodrug strategies (prodrugs of paclitaxel and other taxoids, prodrugs of HIV protease inhibitors), for the synthesis of peptides containing difficult sequences via “O-acyl isopeptide method”, including Alzheimer's disease related amyloid β peptide (Aβ) 1-42, and in the design of pH-, photo- or enzyme-triggered click peptides, as a potential powerful tool for identifying the pathological functions of amyloid β peptides in Alzheimer's disease. This review summarized recent advances in the application of O-N intramolecular acyl migration with special focus on medicinal chemistry.

Isoflavones are an important class of phytoestrogens that are found at extrememly high levels in soy. Up until recently, daidzein and genistein were considered to be the most important and hence most studied isoflavones, however more recently attention has shifted to isoflavone metabolies. Equol represents the main active product of daidzein metabolism, produced via specific microflora in the gut. It has a longer half life and greater biological activity, including superior antioxidant activity. Yet, whilst the majority of animals produce equol following soy consumption, as much as 30 - 50 % of the adult human population cannot. This inability to produce equol in as much as half the population is thought to provide some explanation for the failure of soy to reveal any substantial health benefits in clinical studies. This article will comprehensively review literature investigating the potential cardiovascular benefits of daidzein and its metabolites, paying particular attention to equol. It will focus on the relative vasorelaxant activity, effects on nitric oxide synthase (NOS), antioxidant activity and potential for the treatment and prevention of hypertension and stroke. Findings obtained in both animal and human studies will be reviewed with the hope of gaining an insight into the experimental and clinical importance of equol to the cardiovascular benefits of soy.

Since the first description of self-reactive antibodies in systemic autoimmune rheumatic diseases, many autoantigens have been identified as useful diagnostic biomarkers in clinical immunology. Among the autoantigens, double-stranded desoxoribonucleic acid (dsDNA), the Smith antigen (Sm), topoisomerase-I (topo-I), proliferating cell nuclear antigen (PCNA), and others were described as hallmark targets of systemic autoimmune diseases. The detection of the corresponding autoantibodies can be performed with a variety of immunoassays based on native antigens, recombinant proteins or synthetic peptides. As discussed in this review, synthetic peptides often represent highly accurate antigenic ligands for autoantibody assays that can be easily produced in high quality and quantity and with remarkable reproducibility. Furthermore, the use of peptides that focus on abrogation or neutralization of pathogenic autoantibodies provides a possible new therapeutic approach to the management of autoimmune disorders. There is an increasing number of interesting examples for the application of synthetic peptides in diagnostic approaches. Today's sophisticated epitope mapping methods will potentate the identification of further peptides that can be possibly used as specific targets in diagnostic and therapeutic approaches to improve the patients' treatment. This may lead to a new scientific research area with high impact on the development of diagnostic and therapeutic products, to the area of peptide engineering and “theranostics”.