Reviews & Analysis

TWEAK, a member of the tumour necrosis factor superfamily, is a multifunctional cytokine that acts on cells by binding to a small cell-surface receptor named Fn14. Here, Winkles summarizes the biology of the TWEAK–Fn14 axis and describes the recent evidence supporting the notion that this axis could be a therapeutic target for the treatment of cancer, chronic autoimmune diseases and acute ischaemic stroke.

The renin–angiotensin system, which is a key regulator of blood pressure, has been successfully targeted by several classes of drugs for the treatment of cardiovascular disease. However, renin — the protease at the top of the cascade — although highly attractive as a target, has also proved to be challenging. Here, we describe how these challenges were tackled in the discovery and development of aliskiren, the first renin inhibitor to be approved for clinical use.

The melanocortin system is a central element in the control of energy homeostasis, sexual behaviour and autonomic functions. Here, Wikberg and Mutulis discuss the potential of targeting melanocortin receptors across multiple therapeutic areas, and highlight opportunities and challenges for drug discovery in the melanocortin pathway.

In recent years, the prevalence of multidrug-resistant bacteria has grown considerably, exacerbated by the limited discovery of novel classes of antibacterial agents. Here, Lock and Harry discuss the therapeutic potential of inhibiting bacterial cell division, highlight specific cell-division proteins representing likely antimicrobial targets, and review the recent progress in this exciting new field.

Understanding of the functional significance of the wide structural diversity of G-protein-coupled receptors (GPCRs) — one of the most important families of drug targets — has advanced considerably in recent years. This article provides a comprehensive overview of the five main human GPCR families, discussing gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.

Katz and colleagues summarize knowledge on associations between drug pharmacokinetics and variations in genes coding for proteins involved in drug disposition. They propose a novel strategy in which pharmacogenetic data from early clinical studies is used both to feed back to furtherin vitrostudies of drug pharmacokinetics and to feed forward to optimize later-stage clinical trials, and discuss how this could improve drug development.

Ion channels remain an under-exploited drug target class owing to the low-throughput nature of patch-clamp electrophysiology. In this Review, Dunlop and colleagues evaluate automated electrophysiology platforms and discuss their impact in terms of ion-channel screening, lead optimization and the assessment of cardiac ion-channel safety liability.

Genome wide association (GWA) is emerging as a powerful new tool for identifying genetic variants related to common complex diseases, including diabetes and cancer. This article reviews recent successes that demonstrate the potential of GWA studies to identify genetic biomarkers of disease and reveal novel therapeutic targets and strategies.

The development of prodrugs — chemically modified versions of pharmacologically active agents that must undergo transformationin vivoto release the active drug — is a well-established strategy for improving physicochemical, biopharmaceutical or pharmacokinetic properties of compounds. Rautio and colleagues overview common functional groups that are amenable to prodrug design and highlight the wide range of applications of the prodrug strategy using compounds that are in clinical use or are undergoing clinical trials.

Interleukin 21 (IL21) is an immune-stimulating cytokine that has demonstrated antitumour activity in preclinical models and has recently entered clinical trials. Here, the authors discuss the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.

In this article, Dobson and Kell discuss the evidence to support the idea that carrier-mediated and active uptake of drugs may be more common than is usually assumed and consider the implications for drug discovery and development.

The neuronal and hormonal pathways of the gut–brain axis can provide new therapeutic opportunities for the treatment of upper gastrointestinal disorders. Sanger and Lee provide an overview of potential points of intervention and the progress in developing drugs to target them.

Raising high-density lipoprotein cholesterol (HDL-C) levels has attracted considerable interest as an approach for the treatment of cardiovascular disease. However, the failure of the HDL-raising investigational drug torcetrapib in clinical trials has led to significant doubts about the potential of this strategy. This article considers possible reasons for the failure of torcetrapib, and discusses alternative agents and strategies that might effectively, and safely, raise HDL-C.

The supposedly inert end products of endogenous nitric oxide (NO) metabolism — nitrate and nitrite — have recently been shown to be an important alternative source of NO, complementing the classical NO-synthase pathway. Lundberg and colleagues discuss the emerging role of the nitrate–nitrite–NO pathway, highlighting the therapeutic potential of nitrate and nitrite in various disorders, including myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.

Carbonic anhydrases (CAs) are a large family of ubiquitous metalloenzymes that are involved in many physiological and pathological processes. Traditionally, CA inhibition has been clinically applied in the development of diuretic and antiglaucoma agents. Supuran discusses the emerging potential for inhibitors or activators of CAs to treat a wide range of other disorders, including obesity, cancer, osteoporosis, bacterial and fungal infections, as well as Alzheimer's disease.

The emerging influence of intestinal microorganisms on human health has led to the prospect of modulating gut microbiota composition as a novel therapeutic strategy. In this article, Jia and colleagues discuss the rationale behind this approach, identify conditions to which this may be applied, and suggest technologies and strategies for the development of gut microbiota-targeted therapies.

The success of stem-cell-based therapies depends on finding reliable sources of multipotent and pluripotent cells, and the ability to generate desired derivatives. Here, the authors discuss problems associated with the sourcing of human embyonic stem cells and discuss the current status of stem-cell differentiation technology.

The development of drugs that target chloride channels has lagged behind those of other targets, partly because of technical challenges in screening for chloride-channel modulators. This Review examines the methods for assaying chloride-channel function and emerging drug development opportunities for each of the chloride-channel classes.

The number and frequency of use of protein therapeutics has increased dramatically since the introduction of the first recombinant protein therapeutic — human insulin — 25 years ago. Golan and colleagues overview some of the key characteristics of protein therapeutics, summarize the more than 130 protein therapeutics used currently and suggest a new classification of these proteins based on their pharmacological action.

The association of drugs with lipoproteins can affect their pharmacological and toxicological activities. Here, the authors discuss the mechanisms of drug uptake into lipoproteins and the impact of such interactions, ways to improve the therapeutic profile of hydrophobic drugs, and the ensuing opportunities for drug discovery and development programmes.