Review Articles in 2010

The use of many current autoimmune disease therapies is hampered by their lack of specificity and adverse effects. Here, Faustman and Davis present the new approach of activating tumour necrosis factor receptor 2, to selectively destroy autoreactive immune cells and avoid toxicity.

The key roles of mitochondria in energy production and the regulation of apoptosis are frequently deregulated in cancer. Attempts to activate the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization, could represent a promising strategy for the treatment of cancer.

Alzheimer's disease (AD) presents the largest unmet need in neurology. This article provides an overview of the rationale and the issues that underlie the different strategies for drug discovery in AD, with a focus on approaches aimed at slowing or halting disease progression.

In this Review, the authors discuss recent advances in the characterization of β-arrestin-mediated signalling and biased agonism at seven-transmembrane receptors, and address the implications of these for drug discovery involving this ubiquitous superfamily of receptors.

Ca²⁺ release-activated Ca²⁺(CRAC) channels are involved in a vast array of cellular responses, and abnormal channel activity has now been linked to many diseases including immunodeficiency and autoimmunity disorders, allergy, and cancer. Here, Parekh discusses recent advances in understanding the molecular basis, gating and function of CRAC channels, as well as the therapeutic potential of CRAC channel inhibitors.

Antibiotic drug resistance has increased interest in developing vaccines against carbohydrate structures on the surface of bacterial pathogens. Astronomo and Burton examine recent progress in the identification, synthesis and evaluation of glycan epitopes found not only on bacteria, but also on protozoa, helminths, viruses, fungi and cancer cells for vaccine design.

This Review highlights the Toll-like receptors (TLRs) that hold the most promise for drug discovery research, discussing agents that are in the discovery phase or in clinical trials, as well as new aspects of TLR-mediated signalling that might offer further possibilities of therapeutic manipulation.

A growing number of monoclonal antibodies are being developed for the treatment of malignancies, transplant rejection, autoimmune and other immune disorders; however, they can have severe side effects. Hansel and colleagues consider the mechanisms underlying these effects and strategies to minimize them during preclinical screening and in first-in-human trials.

Membrane transporters play an important part in determining the pharmacokinetics of many drugs. Here, the International Transporter Consortium discusses key transporters with a role in drug absorption and disposition, and provides guidance for clinical drug interaction studies.

Diseases such as Alzheimer's disease and systemic amyloidoses are associated with inappropriate deposition of proteins containing a characteristic highly ordered, β-sheet-rich structural motif. The common structural and pathogenic features of these diverse protein aggregation diseases may offer opportunities to develop overarching therapeutic strategies.

Although currently available antiplatelet therapies have proved effective in preventing cardiovascular events and reducing mortality, they are not without limitations. Here, Michelson discusses recent advances in understanding of the molecular basis of the role of platelets in cardiovascular disease and the resultant emerging novel therapies and strategies.

In this Review the authors discuss the current understanding of the role of the chemokine system in cardiovascular disease and highlight potential therapeutic approaches for atherosclerosis, such as modified chemokine ligands, small-molecule antagonists and disruption of heterophilic chemokine interactions.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening chronic lung disease, for which no specific therapies have been approved. In this article, du Bois discusses the current understanding of the pathophysiology of IPF, the potential of agents under development and possible future therapeutic strategies.

The growing prevalence of multidrug-resistant bacterial strains, together with the decline in the discovery of novel antibacterial agents, has made the effective treatment of many bacterial infections increasingly difficult. Here, Rasko and Sperandio review bacterial virulence mechanisms and discuss the potential of emerging anti-virulence therapeutic strategies.

The therapeutic potential of gene silencing by RNA interference has generated considerable interest and investment, with clinical trials now in progress in various disease areas. However, achieving target specificity remains a key challenge. Here, Jackson and Linsley discuss the off-target effects of small interfering RNAs and strategies aimed to mitigate them.

Despite an arsenal of antiepileptic drugs, ∼30% of patients with epilepsy are not free from seizures. This article reviews the emerging understanding of the molecular basis of epilepsy and experimental models of the disease, and how they might be used in the design of new therapeutics.

Although considerable efforts have been made to deliver drugs to particular tissues, little is known about targeting drugs to specific cellular compartments. By examining the fundamental principles of membrane trafficking and subcellular organization, the authors outline strategies to increase drug concentrations specifically in the relevant subcellular locations.