Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2012

During the past decade, there have been substantial advances in our understanding of the pathogenesis and genetics of eye diseases. Focusing on glaucoma and retinal disorders, Zhang and colleagues review the current status of ocular drug therapy, discuss novel agents currently in development and clinical trials and highlight recent advances in drug delivery.

Metastasis is the main cause of mortality for patients with cancer. For the development of more effective treatments, a better understanding of the mechanisms of metastasis is required. In this Review, Anderson and colleagues discuss the processes underlying metastasis in breast cancer and describe how advances in the identification of relevant signalling pathways and genetic regulators can facilitate the development of novel targeted anti-metastatic drugs.

The sirtuin proteins have emerged as potential regulators of mammalian lifespan, and are believed to be responsible for the health and longevity-enhancing effects of caloric restriction. Here, Baur and colleagues provide an overview of the sirtuin family, focusing on sirtuin 1 (SIRT1) and its potential to be targeted in the treatment of age-related diseases. They address the controversy surrounding the mechanism of action of resveratrol and the development of more potent SIRT1 activators.

A wealth of preclinical data on the role of neuropeptides in modulating behaviour has encouraged extensive efforts to target neuropeptide receptors for the treatment of psychiatric diseases, but so far clinical studies have not led to marketed drugs. This article analyses research on neuropeptide receptor ligands that have been studied in clinical trials, including agents that target the receptors for tachykinins, corticotropin-releasing factor and vasopressin, and suggests new ways to realize their full potential.

In this Case History, Lacey and colleagues chronicle the events that led to an increased understanding of osteoclast biology, beginning with the identification of the pathway mediated by osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL) and RANK. They discuss the strategies that were followed to target this pathway, culminating in the development of the RANKL-specific antibody denosumab, which is now approved for the treatment of osteoporosis and the prevention of cancer-related skeletal events.

The human proprotein convertases are a family of nine serine proteases that are involved in the processing and modulation of various proteins. Seidah and Prat review the physiological functions and pathological implications of proprotein convertases, highlighting recent advances and associated challenges in the development of novel therapeutics targeting them, including inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9) for the treatment of hypercholesterolaemia.

Epigenetic regulation of gene expression can contribute to diseases such as cancer, inflammation and neuropsychiatric disorders. Here, the authors review the protein families that mediate epigenetic signalling through histone acetylation and methylation, and highlight progress in the pharmacological modulation of each class of proteins.

Dual enkephalinase inhibitors and fatty acid amide hydrolase inhibitors increase the levels of endogenous opioids and cannabinoids, respectively. Although their antinociceptive effects have been known for over a decade, they have only recently entered early-stage clinical trials. This Review compares the effects of these two potential classes of novel analgesics and discusses opportunities for combination therapies.

New insights into the mechanisms underlying atrial fibrillation have identified promising new approaches to prevent the fundamental processes that lead to the generation of arrhythmia. Dobrev and colleagues discuss the rationale for developing new anti-atrial fibrillation drugs, the molecular and structural motifs that they target, and the results obtained in experimental and clinical studies.

Antibody Fc receptors (FcRs) connect innate and adaptive immune responses, and present attractive targets for the treatment of inflammatory diseases, cancer and infection. In this Review, Hogarth and Pietersz review the unique opportunities and challenges presented by this receptor class, and discuss the various strategies to manipulate FcR function.

Bone continuously undergoes building and degradation — a process known as bone remodelling. This tightly controlled process can be dysregulated by chronic inflammation, and bone loss is commonly associated with inflammatory diseases. Here, Redlich and Smolen discuss the molecular mechanisms mediating the inflammatory loss of bone and present strategies and agents for therapeutic intervention.

A crucial role of the immune system in cancer progression and response to therapy has recently emerged. Here, Galluzzi and colleagues discuss the immune parameters that may predict the therapeutic response of patients to chemotherapeutics, and review the mechanisms by which current antineoplastic agents activate the immune system against cancer.

Inhibitor of apoptosis (IAP) antagonists have recently entered the stage of clinical evaluation for many different types of cancer. Here, Fulda and Vucic review the different approaches that have been used to target IAP proteins, and discuss their translation into therapeutic anticancer strategies.

Studies of psychiatric disorders have traditionally focused on emotional symptoms, such as depression, anxiety and hallucinations, but poorly controlled cognitive deficits are also prominent and severely compromise quality of life. This article critically discusses our understanding of the nature and causes of cognitive impairment in psychiatric disorders, and reviews the opportunities and challenges in improving cognition in patients, including the development of more effective translational research approaches.

Here, the authors highlight how RNA-blocking oligonucleotides can redirect alternative splicing, repair defective RNA, restore protein production or downregulate gene expression, and so may be useful for treating disorders such as Duchenne muscular dystrophy, spinal muscular atrophy and β-thalassaemia.

Here, the authors highlight the role of proteinase-activated receptors in physiology and in conditions such as cancer and cardiovascular disorders. They also review possible strategies for developing proteinase-activated receptor antagonists and the challenges associated with this goal.

Serine hydrolases are one of the largest and most diverse enzyme classes in nature and have many crucial roles in human physiology and disease. Several serine hydrolases are targets of clinically approved drugs, but many enzymes in this family remain poorly characterized and lack selective inhibitors. Here, Bachovchin and Cravatt discuss the therapeutic potential of serine hydrolases and present novel inhibitor discovery strategies.