Reviews & Analysis

Natural antimicrobial peptides defend host organisms against microbes, but most have modest direct antibiotic activity. This article reviews the latest computer-assisted design strategies to develop enhanced peptide variants, and examines emerging data from clinical trials. These broad-spectrum peptides could lead to the development of next-generation antibiotics.

Interfacial inhibitors bind to the interfaces of macromolecular machines (for example, polymerases or ribosomes) and stall their progress. A number of natural product and synthetic interfacial inhibitors are in the clinic for the treatment of cancer and bacterial infections. Here, Pommier and Marchand review the concept of interfacial inhibition, and discuss the rationale and methods for the discovery of novel interfacial inhibitors.

Here, the authors discuss how aberrant expression and activity of the CCN matricellular proteins contribute to the pathobiology of diseases linked to inflammation or chronic tissue injury, and they highlight how these proteins could be potential therapeutic targets.

Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are associated with the accumulation of misfolded proteins, resulting in neuronal dysfunction and cell death. Thiele and colleagues discuss the therapeutic potential of combating protein misfolding by harnessing the natural cellular protein-folding machinery through pharmacological activation of heat shock transcription factor 1, the master regulator of chaperone protein expression.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known for their role in controlling the rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. They are now emerging as interesting targets not only for the development of drugs to lower heart rate but also for the treatment of diseases related to impaired neuronal activity, such as epilepsy and neuropathic pain.

Induced pluripotent stem cells (iPSCs) – whereby a patient's somatic cells are reprogrammed into an embryonic pluripotent state by the forced expression of a defined set of transcription factors – have the potential to transform drug discovery and development. In this article, Daley and colleagues discuss recent advances and current challenges associated with the generation and use of iPSCs.

Mammalian target of rapamycin (mTOR) has a central role in controlling cellular growth and metabolism. Hall and colleagues describe the advances in therapeutic targeting of this protein, and discuss their potential for the treatment of cancer and beyond.

Here, the authors highlight how there are considerable similarities in the disease mechanisms and pathogenic pathways involved in Huntington's disease and Alzheimer's disease, and advocate that these shared mechanisms could be exploited as common therapeutic targets for drug development.

Although traditionally exploited to improve anticancer drug delivery, the potential uses of nanomedicine in the management of cardiovascular disease are now recognized. Here, Mulder and colleagues review recent advances in applying nanotechnology to the diagnosis and treatment of atherosclerosis.

Predictive biomarkers allow the identification of the subsets of patients who will benefit from a particular drug. However, the development of biomarker–drug combinations requires novel clinical trial designs. In their Perspective, Beckman and colleagues formulate guidelines for the adaptive integration of predictive biomarkers into Phase II/Phase III clinical trials and present strategies to achieve optimal efficiency of such trials.

The ability of tumour cells to maintain a slightly alkaline intracellular pH and an acidic extracellular pH aids the growth of primary tumours and the formation of metastases. Inhibiting pH-regulating proteins in tumours represents a novel therapeutic strategy that is not exploited by the classical anticancer drugs.

Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging knowledge on the oestrogen receptor subtypes α and β suggests that subtype-selective modulators may hold promise for more efficacious and safer treatments of many other diseases and symptoms.

Cancer cells have adapted metabolically to support their characteristic high rate of proliferation. Targeting the metabolic differences between cancer cells and normal cells is emerging as a promising therapeutic approach. Here, Vander Heiden discusses the associated challenges and limitations of this anticancer strategy and reviews evidence supporting specific metabolic enzymes as potential targets.

Analysing data on bioactive compounds can provide insight for developing improved molecules, although much of this data currently resides in proprietary databases. However, even when such data is made available in research articles or public databases, key information is often missing, or the data is not in a format suited to data-mining. With the aim of addressing these issues, this article proposes reporting guidelines for bioactive entities, which have been developed by representatives from industry, academia and data resource providers.

The amyloid cascade hypothesis — which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease (AD) pathology — has strongly influenced recent AD drug discovery efforts. However, so far all agents targeting amyloid-β have failed in Phase III trials. Here, Karran and colleagues re-evaluate the amyloid cascade hypothesis and explore the future potential of amyloid-β-targeting therapeutics.

Transient receptor potential (TRP) channels are a diverse family of cation channels. Here, the authors discuss recent developments in this area, highlight recent developments and setbacks in the field of pain research and analyse TRP channels as targets for skin, pulmonary and urological disorders.

Although our insight into antitumour immune responses has increased substantially in the past few decades, the development of immunotherapy for cancer has been hampered by challenges including the identification of optimal treatment strategies and methods to evaluate them. However, as Punt and colleagues discuss, the recent positive results of clinical trials with novel immunological drugs, as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy, may herald a new era for cancer immunotherapy.

The development of effective therapies for neuromuscular disorders is hampered by considerable challenges, including the abundance of skeletal muscle within the body and the multisystemic nature of many of these diseases. Here, Muntoni and Wood review recent advances in the development of novel therapies that target RNA, which are exemplified by three disorders: Duchenne muscular dystrophy, myotonic dystrophy and spinal muscular atrophy.

The identification of physiological and pharmacological functions of GABA_A (γ-aminobutyric acid, type A) receptor subtypes has renewed the interest in the GABA_Areceptor system as a target for the development of non-sedating anxiolytics, as well as of drugs for indications that are distinct from those of classical benzodiazepines, such as analgesia, schizophrenia and depression.

The exploitation of natural particulates, such as pathogens and mammalian cells, for drug delivery applications is a rapidly emerging field. Here, Yoo and colleagues discuss recent advances in the design of drug carriers based on natural particulates, provide an overview of their current development status and highlight the various applications and limitations of each approach.