Reviews & Analysis

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.

Recent advances in stem cell technology are allowing the production of a variety of human cell types that could provide the basis for more effective drug screening for toxicity and efficacy, as well as more relevant disease modelling based on induced pluripotent stem cells derived from patients.

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.

Advanced therapy medicinal products (ATMPs) offer hope for the treatment of diseases for which therapeutic options are currently lacking. This article discusses the regulatory role of the Committee for Advanced Therapies at the European Medicines Agency, highlighting issues and challenges observed in ATMP development.

Third-party payers typically base their reimbursement decisions for a new drug predominantly on its health benefits relative to existing treatment options — termed relative efficacy (RE). Over the past decade, the role of payers has become more prominent, and drug developers increasingly need to satisfy the sometimes divergent needs of both regulators and payers to achieve market success. This article describes the political background to the RE debate and the challenges of RE assessment, and discusses the impact of RE on drug development.

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.

Long-term therapeutic options for the treatment of obesity are limited. In his Perspective, Cao discusses the functions of the vasculature within adipose tissue — particularly its role in tissue growth and development, and the potential of targeting adipose tissue angiogenesis as a novel anti-obesity therapy.

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.