Current Medicinal Chemistry - Volume 14, Issue 30, 2007

Tumor vascularisation, the formation of blood vessels is a central process to allow tumor growth beyond limited sizes and to facilitate metastasis formation. Angiogenesis is regulated by a balance of stimulatory and inhibitory factors. Angiogenic factors have been the focus of intense research since the prospects of new therapeutic approaches seemed enormous. Vascular endothelial growth factor (VEGF) has emerged as the most potent and most specific growth factor for endothelial cells and therefore a relevant target for novel anticancer therapy. A wide range of agents have been designed for their ability to interfere the VEGF signalling pathway. In addition, several drugs are currently in advanced clinical development. This review describes the current experimental strategies to inhibit VEGF and will also summarize and discuss the results of recent clinical trials involving anti-VEGF compounds either as standalone therapy or in combination with chemotherapy in lung cancer.

γ δ T lymphocytes are involved in the defence from viral and mycobacterial infections; however they are also responsible for autoimmune reactions. Herein, we discuss the characteristics of these cells, focusing on the mechanism(s) underlying extravasation and tissue localization. We show that Vδ1 and Vδ2 γ δT cells display differential expression of adhesion molecules and chemokine receptors, the former being preferentially PECAM-1+CXCR4+, the latter expressing NKRP1A and CXCR3. The two cell populations transmigrate across endothelial cells by activation of distinct kinase pathways and in response to interferon-γ-inducing protein-10 (IP-10/CXCL10) or stromal-derived factor-1 (SDF-1/CXCL12) according to the expression of the specific receptors CXCR3 and CXCR4. IP-10/CXCL10 and SDF-1/CXCL12-induced transmigration are phosphoinositide-3 kinase (PI-3K) and Akt/PKB-dependent. In addition, occupancy of CXCR3, but not of CXCR4, leads to CAMKII activation; blocking of CAMKII decreases IP-10/CXCL10 and 6Ckine/SLC/CCL21- driven transmigration. We report that HIV-1-infected patients have an increased number of circulating Vδ1 T cells possibly due to the interference of Tat protein on the function of chemokine receptors. In turn, patients with relapsing-remitting multiple sclerosis (MS), display an increase in peripheral Vδ2 γ δ T cells and this is related to interleukin-12-mediated upregulation of NKRP1A. Finally, the possible role of γ δ T lymphocytes in post-transplantation immune reconstitution is discussed.

Stroke is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. In 2002, a candidate locus for stroke (STRK1) was identified with a significant logarithm of odds (LOD) score at 5q12 in Caucasians, and in 2003, the PDE4D gene was subsequently identified as a susceptibility gene at this locus. Some investigators have recently examined whether polymorphisms in the PDE4D gene are associated with stroke in population studies. Some of these studies have reported the polymorphisms to be associated with a risk of stroke, while others have reported the exact opposite. These discrepancies have been attributed to racial differences or differences in methodologies and analyses. In 2006, a powerful method for isolating the susceptibility region at 5q12 was reported in a haplotype-based case-control study. In the present paper, we review both current issues and progress in the isolation of susceptibility genes for ischemic stroke, with particular emphasis on the PDE4D gene in the STRK1 region of 5q12.

Pharmacological therapies in ischemic stroke have made limited progress in recent years. After many negative neuroprotection trials in humans, considerable concerns have been raised about future research strategies. This led to expert rounds, the so-called STAIR conferences, which critically reviewed previous studies and provided research recommendations. Hopes were raised that STAIR might lead to breakthroughs in neuroprotection strategies in the near future. Whether this will indeed become true, remains to be awaited. An important aspect in the context of brain pharmacotherapies is the blood-brain barrier, which prevents drugs from brain entrance. The blood-brain barrier not only acts as passive diffusion barrier, it expresses active transporters that eliminate drugs from the brain and thereby profoundly influence drug tissue levels. These transporters exhibit strong variabilities between animals and humans, which make it hardly possible to predict brain concentrations of drugs over species barriers. As such, drug biodistribution turns out to be a major confounder in pharmacological therapies. This paper claims that more precise brain accumulation studies are needed in preparation for clinical trials both in animals and in humans. This might lead to better dose selections and higher success rates of future pharmacological trials.

Amyotrophic lateral sclerosis (ALS) is a severe clinical condition characterized by upper and lower motor neuron degeneration for which there is no truly effective treatment. The absence of an effective treatment can be explained in part by the complex and heterogeneous genetic, biochemical, and clinical features of ALS. While ALS accounts for the majority of the motor neuron diseases, the recognition of disease variants and mimic syndromes may lead to further insights into possible causes for the generality of ALS. From a biochemical perspective, the process of motor neuron degeneration is complex and the multifactorial influences and potential biomarkers of ALS have never been assessed in the light of the clinical heterogeneity of ALS. Several genes and environmental influences have been suggested as possible risk factors of ALS. A better understanding of interactions between these risk factors, potential biomarkers and heterogeneous clinical features may lead to more clearly defined pathological profiles among individuals or groups of ALS patients and in turn lead to more focused therapeutic trials.

Opiate alkaloids, such as morphine, are powerful analgesic agents that are the drugs of choice for the treatment of severe pain. The pharmacological effects of opiates are mediated through the binding and activation of membrane-bound opioid receptors that are found in the central and peripheral nervous systems. Opioid receptors have been classified into three different types, μ, δ and κ, and are activated by the specific ligands. It has been demonstrated that the most potent antinociceptive effects are mediated by the μ-receptor. However, until 1997 no endogenous ligand for this receptor was known. The identification of endomorphins opened a new era in the research of the μ-opioid system. They are the first reported brain peptides that label μ-receptor with high affinity and selectivity and therefore are proposed as the endogenous μ-opioid receptor ligands. Morphine and endomorphins act as agonists at the same μ-opioid receptor, but the latter are thought to inhibit pain without some of the undesired side-effects of plant opiates. This observation encouraged extensive studies on the possible use of endomorphin analogs as analgesics instead of morphine. This review summarizes a decade of research on structure-activity relationship studies of endomorphin analogs, aimed at obtaining compounds with increased bioavailability, in particular with better barrier penetration and resistance against enzymatic degradation. Chemical modifications that led to obtaining potent and selective agonists and antagonists based on the structure of endomorphins are discussed.

Lysophosphatidylcholine (LPC) is a bioactive proinflammatory lipid generated by pathological activities. LPC is also a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL) and is implicated as a critical factor in the atherogenic activity of Ox-LDL. LPC is believed to play an important role in atherosclerosis and inflammatory diseases by altering various functions in a number of cell-types, including endothelial cells, smooth muscle cells, monocytes, macrophages, and T-cells. LPC activates several second messengers -- including protein kinase C, extracellular-signal-regulated kinases, protein tyrosine kinases, and Ca2+ -- implicating the engagement of transduction mechanisms in its observed actions. Moreover, recent evidence suggests that in several cell-types, cloned orphan G-protein-coupled receptors may serve as the specific receptors via which LPC modulates second messenger pathways (although LPC may not be a direct ligand of such receptors). In addition, current evidence suggests that LPC impairs the endothelium-dependent relaxations mediated by endothelium-derived relaxing factors and directly modulates contractile responses in vascular smooth muscle. However, despite all this, and although elevated levels of LPC have been linked to the cardiovascular complications associated with atherosclerosis, ischemia, and diabetes, the precise pathophysiological roles played by LPC in several states remain to be established. In this review, we focus in some detail on the entirety of the signal-transduction system for LPC, its pathophysiological implications, and the vascular abnormalities associated with it.

The genetic code plots the relationship between a triplet base sequence on RNA and an amino acid that corresponds to a protein associated with a required function in organisms. Accurate knowledge about the genetic code, including its origin and evolutionary process, would be helpful for determining the causes of genetic disorders and discovering new medical treatments, as well as for understanding the origin of life. This review begins with discussion of several well-known theories on the origin of the genetic code. Then, a GNC-SNS primitive genetic code hypothesis, which we originally proposed, is explained in relation to the weak points of other theories. S and N denote G or C and any of the four bases, respectively. We also introduce our hypothesis of the GADV-protein world hypothesis on the origin of life, where GADV stands for the four amino acids, Gly[G], Ala[A], Asp[D] and Val[V]. Next, we discuss the reason why genetic disorders, which should be triggered by base replacements, are repressed at a low level under the universal genetic code. Finally, we explain the current difficulties we faced in treating genetic disorders, suggesting a prospect for a new type of treatments of these disorders.

A wide variety of proteins can bind high-mannose oligosaccharides and are broadly neutralizing against HIV-1. However, success in eliciting broadly neutralizing antibodies against HIV-1 has been limited to date. The rational design of an HIV-1 vaccine is based on the information gained through the structural analysis of antibodies complexed with their epitopes. Of particular interest to this review are the binding of mannosides to human monoclonal antibody 2G12 recognizing Man9GlcNAc2 from HIV-1 gp120. It is widely recognized that T-cell-independent antigens carbohydrates are poorly immunogenic, and fail to induce memory. To increase the immunogenicity, carbohydrate antigens have to be coupled to a highly immunogenic carrier. The design of peptide carbohydrate mimotopes (mimetics of carbohydrate antigens) is one approach that is currently explored to elicit neutralizing antibodies. This work is concerned with existing structural data on Man9GlcNAc2 as the most promising epitope (or glycotope). Structural analysis of various torsion angles of Man9GlcNAc2 is explored. The focus is made primarily on the third variable region (V3 loop) of gp120 due to its crucial relevance for coreceptor usage, as a principal neutralizing determinant (PND), and for its conserved glycosylation sites N295, N302 and N332. Valuable structural information from glycosylation effects is taken into account for the development of a V3 loop rational structure-based vaccine strategy using N295 and N302 as potential conformational epitope.

Artemisinin is a sesquiterpene compound of plant origin. It has a low molecular weight, and it contains five oxygen atoms, two in a lactone function, one is part of a seven membered ring system and two forms a peroxide function bridging over the seven-membered ring. It is a highly energetic molecule prone to lose its activity if circumstances permit. Reduction of its lactone function into dihydroartemisinin makes derivatization easy. Esterification and ether formation contribute to stability. Dihydroartemisinin exists preferably in a beta epimeric format but flip-flops with the alpha epimer. Solvation effects play a role. In doing so, open forms are created and they contribute to the instability, both of the peroxide and of the seven-membered ring. Artemisinins constitute a remarkable class of compounds which display instability both biologically and chemically due to the presence of various functional groups. Activity ranges from a wonderful action against a series of parasites, in particular malaria and schistosomiasis, to bacteria, fungi and selected viruses. The latest developments indicate a potential use in adjuvant cancer chemotherapy. The built-in chemical instability, necessary for biological action, causes serious pharmaceutical problems and only a restricted number of derivatives are useful. Problems are accelerated under tropical conditions and the basic active drug dihydroartemisinin cannot be used as such since it is prone to accelerated breakdown into a series of inactive products. The pitfalls of chemical instability and pharmaceutical stability are discussed in relation to the current uses of the drugs.