Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2006

An attractive strategy to render drug-resistant bacteria susceptible to antibiotics is to inhibit the bacterial efflux pump. Lomovskaya and colleagues review the available structural data on the most effective class of bacterial efflux pumps and discuss current development of small-molecule efflux inhibitors.

Genomics promised to revitalize the search for new antibiotics but still no new drug class against a novel target has materialized. Payne and colleagues describe the frustrations of their genomics efforts at GlaxoSmithKline and how this changed their approach to antibacterial R&D.

There are currently serious concerns about the control measures that should be taken if a pandemic of influenza A were to strike. De Clercq discusses the therapeutic potential of agents that have been shown to be active against influenza A viruses, and describes emerging strategies for targeting these viruses.

The Wnt signalling pathway has a central role in tissue development and tissue maintenance, but is frequently dysregulated in several types of cancer, particularly those of the digestive tract. Here, Barker and Clevers examine the recent progress in the development of Wnt inhibitors as anticancer drugs.

Recent developments in the understanding of the mechanisms of cardiac arrhythmias have opened up unprecedented opportunities for drug development. Here, Nattel and Carlsson review emerging findings in the development of new types of anti-arrhythmic compounds targeting two particularly important cardiac arrhythmias: atrial fibrillation and ventricular fibrillation.

The hedgehog signalling pathway is abnormally activated in most basal cell carcinomas, in one-third or more medulloblastomas, and has been implicated in several other types of cancer. Rubin and de Sauvage discuss the therapeutic opportunities presented by recent insights into this pathway, and the compounds currently in development.

The potential market for obesity drugs is huge, and current therapies are limited by their side effects and modest efficacy. Cooke and Bloom provide insights into current anti-obesity strategies, with a focus gut peptides as a promising source for future obesity therapies.

Lead discovery is a major bottleneck in the pipeline for novel drugs for tropical diseases such as malaria. Nwaka and Hudson discuss how lead-discovery strategies based on highly integrated partnerships and networks involving academia and industry in industrialized and disease-endemic countries could increase the chances of success.

Animal models contribute to advancing our understanding of the pathophysiology of complex disorders and the preclinical assessment of therapeutics for these diseases. Van Dam and De Deyn review the major rodent models of Alzheimer's disease and evaluate their usefulness for drug discovery research

The global infectious disease burden primarily falls on the developing world. Deen and Clemens discuss several issues in the design and implementation of vaccine trials in less developed countries, as well as ethical issues arising from such trials.

Phosphatidylinositol 3-kinase (PI3K)γ is an emerging target for the development of drugs with anti-inflammatory and/or cardioprotective activity. Rommel and colleagues review the biology of this key signalling molecule and discuss current efforts to develop selective PI3Kγ inhibitors.

Inflammatory diseases of lung, liver, heart, joints and periodontium have high prevalence, but many current treatments have limited efficacy and are expensive. McCulloch and colleagues consider new anti-inflammatory drug targets based on the clustering of interleukin- 1 receptors into multi-protein aggregates associated with cell adhesions.

Schapira and colleagues describe recent advances in the development of novel doperminergic and non-doperminergic drugs for the treatment of Parkinson's disease and related motor complications.

Despite considerable progress in the treatment of paediatric leukaemias, a major need still exists for therapies for patients who relapse. Bonate and colleagues describe the discovery and development of the nucleoside analogue clofarabine, which is the first such drug approved for paediatric leukaemia in more than a decade, and the first to receive approval for paediatric use before adult use.

In December 2005, sorafenib became the first new treatment to be approved for advanced renal cancer in more than a decade. Wilhelm and colleagues provide the history of this drug, which inhibits several kinases involved in tumour signalling and angiogenesis.

Evgenovet al. review the discovery, biochemistry and pharmacology of nitric oxide-independent stimulators and activators of soluble guanylate cyclase, a key signal-transduction enzyme, and discuss their potential for treating arterial and pulmonary hypertension, heart failure, atherosclerosis, thrombosis, erectile dysfunction, renal fibrosis and failure, and liver cirrhosis.

Johnstone and colleagues discuss the molecular events that underlie the anticancer effects of histone deacetylase inhibitors, and consider how the clinical development and application of these agents may be optimized, either as monotherapies or in combination with other anticancer drugs.

Far from being simple degradative enzymes, proteases are now seen as key signalling molecules and desirable drug targets in several diseases. Turk discusses our success so far at targeting proteases and how these enzymes might be exploited therapeutically in the future.

The poor predictive ability of traditional xenograft mouse models is thought to be a key factor underlying failures of novel cancer drugs in clinical trials. Sharpless and DePinho describe the opportunities and challenges in the application of novel genetically engineered mouse models that more faithfully mimic human cancers, and their potential to improve the success of cancer drug development.

Phosphodiesterase 5 inhibitors augment endogenous nitric oxide signalling, thereby restoring vascular reactivity to diseased blood vessels. Ghofrani and colleagues review the evolution of the PDE5 inhibitor sildenafil from a potential anti-angina drug, to an on-demand oral treatment for erectile dysfunction, and its recent re-positioning as a pulmonary hypertension therapeutic.