Reviews & Analysis

The incidence of invasive fungal infections is increasing, and there is an unmet need for new antifungal drugs. This article provides an overview of the history of antifungal drug discovery, discusses the current pipeline and presents new vaccination and immunotherapeutic approaches to treat fungal infections.

The permeation of a drug across a biological membrane is one of the most important determinants of the pharmacokinetics of a drug. Here, the authors discuss the contribution of passive transport and carrier-mediated transport to the total permeation of a drug, focusing onin vitro and in vivoresults, as well as highlighting the implications for drug discovery.

Polo-like kinase 1 (PLK1), which helps orchestrate key events in the cell cycle, has been preclinically validated as an anticancer target, whereas it seems that the closely related kinases PLK2 and PLK3 might act as tumour suppressors. Strebhardt reviews recent insights into the biology of PLKs, with emphasis on their role in malignant transformation, and examines progress in the development of small-molecule PLK1 inhibitors as anticancer drugs.

Advances in nanoparticle engineering, and in understanding of the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications such as targeted drug delivery. Petros and DeSimone review the impact of nanoparticle characteristics on their biological properties and recent progress in the rational design of nanoparticle therapeutics, discussing the challenges to realizing their potential.

Advances in therapeutic strategies for Alzheimer's disease depend on the identification and qualification of biomarkers. Here, the authors review the current status of candidate biomarkers for Alzheimer's disease and provide the perspectives of different stakeholders on biomarker discovery and development.

Aptamers are oligonucleotide sequences that are capable of recognizing target proteins with an affinity and specificity rivalling that of antibodies. In this article, Keefe and colleagues discuss the development, properties and therapeutic potential of aptamers, highlighting those currently in the clinic.

All available antidepressants act through monoaminergic mechanisms, and there is considerable interest in novel approaches that might improve treatment. One such strategy focuses on melatonin, a key regulator of circadian rhythms, which are perturbed in depression. This article describes the history of agomelatine, which possesses both melatonergic agonist and 5-hydroxytryptamine 2C antagonist properties. It was granted marketing authorization in Europe in 2009, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

The development of drugs for rare diseases — often known as orphan drugs — is attracting increasing interest and investment, catalysed in part by incentives such as those provided by the 1983 US Orphan Drug Act. This article provides the first comprehensive analysis of 25 years of data on the designation and approval of orphan drugs by the US Food and Drug Administration, with the aim of supporting and encouraging future orphan drug development and approval.

Efforts to repeat the success of pioneering molecularly targeted cancer drugs, such as trastuzumab, for particular patient populations have been hampered by factors such as a lack of correlation between the molecular markers used to select patients for treatment and the drug response. This article highlights lessons learned from the development of drugs targeting members of the epidermal growth factor receptor family, and discusses strategies to decrease the risk of failure in clinical trials by more effectively integrating molecular diagnostics into anticancer drug discovery and development.

Biomarker strategies are increasingly being applied in drug development to address the challenges posed by heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US FDA initiated a programme in 2004 to allow sponsors to submit exploratory data voluntarily, without immediate regulatory impact. This article discusses a selection of case studies from the first 5 years of this programme, highlighting lessons learned.

Most current obesity therapies aim to reduce calorific intake or absorption and are limited by poor efficacy or unpleasant side effects. Here, Tseng and colleagues discuss the therapeutic potential of the alternative approach of increasing cellular energy expenditure, principally by stimulating adaptive thermogenesis, to prevent or treat this disorder.

Preventing the reabsorption of glucose in the kidney by inhibiting the sodium–glucose co-transporters (SGLTs) is emerging as a promising new strategy to treat type 2 diabetes. Here, Chao and Henry give an overview of the role of the kidney in glucose homeostasis and discuss the development and potential of SGLT2-selective inhibitors, reviewing those agents currently undergoing clinical investigation.

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.

This article explores some of the challenges and opportunities in developing personalized treatment for patients with cancer, which could improve outcomes, reduce toxicity, improve efficiency in drug development and help control the rising costs of cancer care.

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.

Computational chemistry — in particular, virtual screening — can provide valuable contributions in hit and lead discovery. However, it seems that there are relatively few examples so far of drug discovery projects in which virtual screening has been the key contributor. This article discusses aspects that could be limiting the potential of virtual screening, and proposes key directions in which significant progress could be made.

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.