Current Medicinal Chemistry - Volume 14, Issue 8, 2007

Enteroviruses are members of picornavirus family which causes diverse and severe diseases in humans and animals. Clinical manifestations of enterovirus infections include fever, hand, foot, and mouth disease, and herpangina. Enteroviruses also cause potentially severe and life-threatening infections such as meningitis, encephalitis, myocarditis, polio-like syndrome, and neonatal sepsis. With the emergence of enterovirus all over the world as the major causative agent of HFMD fatalities in recent years and in the absence of any effective anti-enteroviral therapy, there is clearly a need to find a specific antiviral therapy. Steps such as viral attachment, uncoating, viral RNA replication, and protein synthesis in the replication cycle can serve as potential targets for antiviral agents. Agents targeted at viral protein 1 (VP1), a relatively conserved capsid structure mediating viral adsorption and uncoating process, is of great potential to be antienterovirus drugs. Recently, considerable efforts have been made in the development of antiviral compounds targeting the capsid protein of enterovirus. This review summarizes the development of small molecules targeting enteroviral capsid protein as effective antiviral therapy.

Ischemic stroke is characterized by the disruption of cerebral blood flow, which produces a central core of dead neurons surrounded by a penumbra of damaged but partially functional neurons. Many factors are associated with such brain injury, including excitotoxicity and free radicals. Recent clinical studies have shown that high plasma ferritin levels are detrimental in acute ischemic stroke. As an iron-storage protein, ferritin can act both as a scavenger and as a donor of free iron, which is a source of hydroxyl radicals. Following disruption of the blood-brain barrier, the ferritin and the free iron that have accumulated in endothelial cells in brain capillaries, together with plasma ferritin, can enter the penumbra. Iron-dependent oxidative stress in the penumbra can lead to necrosis and further neurological deterioration following ischemic stroke. An excess of iron should be considered pathological in the ischemic brain. Therapeutic strategies for ischemic stroke should attempt to restore brain function within the penumbra. Consequently, the iron content of systemic stores should be measured, and anti-oxidant treatment should be considered when it is excessive.

Screening strategies of therapeutic molecules and targets have received increasing attention during the past few years. Indeed, identification of novel compounds and drug targets involved in apoptosis control is a major rate-limiting step in anticancer drug development efforts. In this review, we discuss the current screening methodologies to discover novel potential therapeutics targets and drugs implicated in the apoptotic pathway, in particular the intrinsic pathway. In addition, we present a proteomic screening strategy that led us to identify a mitochondrial glutathione-S-transferase as a novel regulator of the pro-apoptotic adenine nucleotide translocase pore function.

In the cell, the unwinding of double-stranded polynucleotides is catalyzed by helicases that are present in all kingdoms of life from virus to man. Viruses, like all other organisms, synthesize their DNA or RNA genomes in a template-dependent manner. In addition to DNA or RNA polymerases, a helicase is therefore required to displace the single-stranded genome after replication, thus leading to the formation of progeny viral particles. In drug design against viral helicases, a number of viral helicase inhibitors have been developed and used in clinical studies. In humans, DNA helicases play essential roles in facilitating cellular DNA metabolisms including genome replication, DNA repair, recombination, transcription as well as telomere maintenance. The care-taker roles of helicases suggest that they might be suitable for targeting to prevent cell proliferation during carcinogenesis. Identifying helicase specific-inhibitors may lead to the development of drugs in the treatment of human cancers. In addition, some helicases such as BLM and WRN interact physically and functionally with telomerases and are involved in telomere maintenance. Hence, an antitumor therapy designed to interfere with both helicases and telomerases may be much more effective than the helicase or telomerase inhibitors alone. This review addresses these topics and discusses the design of antiviral and antitumoral agents based on the knowledge of structures and functions of helicases.

This review gives a brief overview of the expression patterns, molecular pharmacology and physiological role of the cannabinoid 2 receptor (CB2) in pain. Particular emphasis is given to the therapeutic utility of CB2 receptor agonists. Through studies utilizing selective CB2 receptor agonists, non-selective cannabinoid agonists in conjunction with selective CB1 and CB2 receptor antagonists, or CB2 receptor knockout mice, it is now clear that this receptor plays a critical role in nociception. To this end, CB2 receptors have been shown to modulate acute pain, chronic inflammatory pain, post-surgical pain, cancer pain and pain associated with nerve injury. Here we review these studies and the compounds that were utilized. We hypothesize the mechanism of action by which the CB2 receptor could be involved in these processes. Finally we summarize the most recent novel chemical scaffolds that are being investigated towards advancing selective CB2 receptor agonists into the clinic. Many new pharmacological agents have been identified by high throughput screening and small molecule lead discovery and optimization in the past 10 years. It is anticipated that at least some of these agents may ultimately constitute effective new pain therapeutics that lack the side effects associated with traditional cannabinoid ligands.

Biosensors are of great interest for their ability to monitor clinically important analytes such as blood gases, electrolytes, and metabolites. A classic example is to monitor the dynamics of blood-glucose levels for treating diabetes. However, the current practice, based on a three decade old technology, requires a drop of blood on a test strip, which is in dire need of replacement. The increasing demands and interests in developing implantable glucose sensors for treating diabetes has led to notable progress in this area, and various electrochemical sensors have been developed for intravascular and subcutaneous applications. However, implantations are plagued by biofouling, tissue destruction and infection around the implanted sensors and the response signals must be interpreted in terms of blood or plasma concentrations for clinical utility, rather than tissue fluid levels. This review focuses on the potentials and pitfalls of implantable electrochemical sensors and presents our opinions about future possibilities of such implantable devices with respect to biocompatibility issues, long-term calibration, and other aging effects on the sensors.

Current Medicinal Chemistry, 2005, 12 (25), 2923-2924. Contents Tumour Necrosis Factor Alpha Converting Enzyme Guest Editor : David Fairlie This should read Current Medicinal Chemistry, 2005, 12 (25), 2923-2924. Contents Latest Developments in the Treatment of Inflammatory Disease Guest Editor : David P. Fairlie