Reviews & Analysis

Adipose tissue may become severely dysfunctional during obesity, resulting in disrupted metabolic homeostasis and ultimately type 2 diabetes. Here, Scherer and colleagues provide an overview of adipose tissue development, function and homeostasis, focusing on emerging potential strategies for targeting this organ in the treatment of obesity-associated diabetes.

Current treatments for chronic kidney disease (CKD) only delay disease progression and can be associated with significant side effects. Here, Suzstak and Breyer discuss emerging novel targets and strategies for the treatment of CKD. Key challenges faced in the development of CKD therapies and future clinical trial designs are considered.

The biological rationale for targeting protein–protein interactions as a therapeutic strategy is strong, but identifying viable small-molecule drugs to achieve this has proved highly challenging. This article uses examples of successful discovery efforts to illustrate the research strategies that have proved most useful for different classes of protein–protein interactions.

Anti-inflammatory treatments reduce inflammation but do not necessarily encourage resolution. Here, Fullerton and Gilroy suggest that some chronic inflammatory disorders may be characterized by an inability to resolve inflammation, and discuss the biology of resolution and translational efforts to target it.

Insulin continues to represent a cornerstone therapy for diabetes, but its use is limited by its narrow therapeutic index. Here, DiMarchi and colleagues provide an overview of the history of the development and use of insulin as an antidiabetic agent, focusing on recent approaches to improve the efficacy, safety and convenience of insulin therapy.

Current therapies for obesity have limited efficacy and may be associated with substantial adverse effects. Cinti and colleagues discuss the conversion of white fat to brown, thermogenic fat as a potential strategy to curb obesity. Adipocyte conversion could be particularly important in the visceral compartment, as fat in this region is associated with morbidity but is also particularly prone to transdifferentiation.

Metabolomics is rapidly emerging as an important tool in understanding disease mechanisms and identifying novel therapeutic strategies. Here, Wishart explores recent developments in metabolomics technologies, focusing on the growing role of metabolomics in drug discovery and its potential effect on precision medicine.

Immuno-oncology has become the fastest-growing area in the pharmaceutical industry. In this Perspective, Hoos provides an overview of the history of immuno-oncology and investigates the factors that have led to its success. Moreover, he discusses the three generations of immunotherapies that have been developed since 2011 and provides an outlook to the future directions of drug discovery and development in immuno-oncology.

Advances in the understanding of the genetic and environmental causes of schizophrenia, and their relationship to aberrant patterns of neurodevelopment, have led to growing interest in the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than just alleviating its symptoms. This article provides a broad-based consideration of the challenges and opportunities inherent in such efforts.

This article discusses evolving preclinical strategies for detecting drug-induced cardiotoxicity using human ion-channel assays, human-basedin silicoreconstructions and human stem cell-derived cardiomyocytes. Such strategies have the potential to improve the early detection of genuine cardiotoxicity risks, reducing the likelihood of mistakenly discarding viable drug candidates and speeding worthy drugs into clinical trials.

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development.

Members of the integrin family of receptors, which are involved in cell–cell adhesion, have been successfully targeted for cardiovascular disease, multiple sclerosis and inflammatory bowel disease. Ley and colleagues review the biological basis for the development of the next generation of integrin-targeted drugs, highlighting lessons learned from successes and failures.

Modulators of glucagon-like peptide 1 (GLP1) and the resulting G protein-coupled receptor (GPCR) signalling have recently come to the fore of the treatment of type 2 diabetes. In this Opinion article, Oh and Olefsky discuss the potential for intervention with other GPCRs for the treatment of this disease, highlighting GPCR-mediated effects on insulin secretion, insulin sensitivity and inflammation.

The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype — epithelial–mesenchymal transition — has a key role in tumour progression and is therefore becoming a promising anticancer target. This article discusses the screening and classification of compounds that affect epithelial–mesenchymal transition, highlights some compounds of particular interest and discusses issues related to their clinical application.

Research on the blood–brain barrier (BBB) has led to the concept of a complex, dynamic interface between the central nervous system (CNS) and periphery. Banks considers how this new understanding can combine with classical concepts to inform CNS drug delivery strategies and promote BBB integrity in various diseases.

Non-alcoholic steatohepatitis (NASH) is increasing in prevalence, partially because of the pervasiveness of obesity. In this Review, Musso and colleagues discuss potential future approaches to treat this disease, including those that target causes, such as inflammation and aberrant metabolism, as well as those that target fibrosis, one of the key features of patients with NASH.

Forms of cell death besides apoptosis and necrosis are becoming increasingly well understood, and are relevant to many disease contexts. Here, Conradet al. describe the mechanisms underlying regulated forms of necrosis — including necroptosis, ferroptosis, parthanatos and cyclophilin D-mediated necrosis — and efforts to induce or prevent them in disease.

Over the past 10 years, targeting vascular endothelial growth factor A (VEGFA) has been widely pursued in the treatment of various cancers and ophthalmic diseases. Here, Ferrara and Adamis provide an overview of the discovery of VEGFA and the development of anti-VEGFA therapies, addressing key challenges and issues that remain in the application of these agents.