Reviews & Analysis

Tetraspanins are a family of transmembrane proteins with emerging roles in both normal and pathological processes including development, fertilization, malignancy, immune-cell function and infectious disease. Here, Hemler reviews the functions of specific tetraspanins with the potential to be therapeutically targeted, and proposes possible strategies that may be pursued.

Here, Haskó and colleagues discuss how an increased awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

In this Review, Lambert describes the physiology and potential clinical applications of nociceptin/orphanin FQ and its receptor. This peptide–receptor system has been implicated in a wide range of biological functions such as pain, drug abuse, cardiovascular control and immunity.

The recent awareness that bile acids act as complex metabolic integrators and signalling factors has led to the recognition of bile-acid signalling as a potential novel therapeutic target in metabolic disease. Thomas and colleagues overview the metabolic roles of bile acids and discuss approaches to modulate their signalling pathways in the treatment of disorders including obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis.

Pseudoreceptor models can provide a valuable tool for drug design in cases where a high-resolution structure of the target is not available. This article reviews pseudoreceptor modelling techniques, presenting recent applications in hit and lead finding, and critically discusses the prerequisites, advantages and limitations of the various approaches.

Neuroprotective agents that slow cell death, vital for the treatment of a range of neurodegenerative disorders, are currently lacking. Dragunow discusses some of the factors contributing to the failure of translation from the laboratory to the clinic, and suggests approaches to introduce an adult human preclinical platform to overcome translation obstacles in neurodegenerative drug development.

Natural products comprised of a macrocycle ring structure have proven their therapeutic applications as antibiotics, immunosuppressants as well as anticancer agents. Despite this, macrocyclic compounds remain under-explored. Terrett and colleagues review the properties and features of current macrocycle drugs, emphasizing the vast potential of synthetic macrocyles in drug discovery.

There is increasing interest in the role of purinergic signalling in CNS disorders, but few modulators have reached the clinic. Here, Burnstock provides an overview of the role of purinergic signalling in specific disorders, including brain trauma, ischaemia, neurodegenerative, neuroinflammatory and neuropsychiatric diseases, and highlights specific purinergic receptor subtypes that represent promising therapeutic targets.

Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility.

In this Perspective, Max and Stewart discuss how methods of molecular epidemiology, proved effective in the study of other diseases, can enhance the returns from human genomic studies and expedite the development of new drugs to prevent or treat pain.

Recent advances in genomic knowledge and associated technologies should help accelerate the development of genetic tests that can predict drug response and toxicity; however several challenges remain. Here, Weiss and colleagues discuss the factors that affect the development, performance and uptake of pharmacogenetic tests.

Specialty pharmaceuticals — drugs prescribed primarily by specialists rather than primary-care physicians — have become an increasingly important part of the global pharmaceutical landscape. Ma and colleagues analyse the key factors influencing the commercial success and failure for specialty pharmaceuticals.

MET tyrosine kinase has a central role in cell motility, proliferation and protection from apoptosis — properties that can transform it into a powerful pro-metastatic agent or oncogene. Here, Comoglio and colleagues discuss its biological role in cancer progression, recent progress in MET-targeted therapies, and how to identify the patient populations that might benefit from such treatment.

Fatty acid-binding proteins (FABPs) are members of a highly conserved family of proteins central to lipid-mediated processes and related metabolic and immune response pathways. Here, the authors review the functions of individual FABP family members, emphasizing the potential of FABP inhibition as a novel strategy in the treatment of disorders of the metabolic syndrome including obesity, diabetes and atherosclerosis.

In this Review Ebert and Wafford discuss the mechanisms of action of current and emerging hypnotic drugs, emphasizing the importance of taking into account the consequences of disrupted sleep on day-time performance (or quality of wakefulness) when developing new therapeutics.

Successful development of novel anti-atherosclerosis therapies is hampered by the lack of imaging biomarkers for their evaluation. In their article, Lindsay and Choudhury compare and contrast the ability of current atherosclerosis imaging modalities to predict clinical outcomes and discuss the potential of emerging technologies to aid anti-atherosclerosis drug development by quantifying changes in biological function at the level of the atherosclerotic plaque.

The United States Congress is currently considering legislation to create a regulatory pathway for follow-on biologics. Grabowski discusses the importance of data exclusivity in allowing innovator companies to achieve a return on investment before entry of follow-on competitors, and presents an analysis that provides support for a substantial data exclusivity period.

There is mounting evidence of the involvement of the glutamatergic system in mood-disorder pathophysiology as well as of the efficacy of glutamatergic agents in mood disorders. In this Review, the authors examine the contribution of abnormalities in the glutamatergic system to the impairments in neural plasticity that are observed in patients with mood disorders, and how this knowledge can be applied to the development of antidepressants with more rapid and sustained effects.

High-throughput profiling of compound libraries against large panels of kinases is becoming technically feasible. In contrast to the traditional linear, target-centric approach to discovery, this approach may provide a choice of targets to pursue that is guided by the quality of lead compounds available, rather than by target biology alone, and could thereby significantly improve the productivity of kinase inhibitor discovery.

In this Review, the author discusses how prolonging the lifespan of endocannabinoids or toning down their action may be beneficial in a range of conditions such as pain, affective and neurodegenerative disorders, gastrointestinal inflammation, and obesity and metabolic dysfunctions.