Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2015

Solute carrier (SLC) transporters mediate a large number of physiological processes, and the dysfunction of individual transporters has been implicated in many Mendelian diseases. In this Review, Giacomini and colleagues summarize these roles and ways in which SLC transporters can be targeted by drugs, and highlight current and investigational drugs that modulate SLC transporters.

Attempts to reduce the number of efficacy- and safety-related failures that may be linked to the physicochemical properties of small-molecule drug candidates have been inconclusive owing to the limited size of data sets from individual companies. Waring and colleagues analyse the largest data set compiled so far on the causes of attrition for oral, small-molecule drug candidates, derived from a pioneering data-sharing effort by AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer.

Despite considerable advances in malaria medicines in the past 20 years, the global burden of malaria remains substantial. Moreover, continued emergence of drug resistance ensures that new antimalarials will be needed in the near future. Wells and colleagues summarize the current landscape of antimalarial therapies and investigational drugs, highlighting the progress made, identifying gaps in terms of target profiles and recommending priorities for future research.

Although natural killer (NK) cells can induce immune responses against malignancies, their therapeutic potential in the clinic is largely unexplored. In this Review, Childs and Carlsten discuss recent insights into NK cell biology and how these can be used for the development of new immunotherapeutic strategies against cancer.

Inhibiting the progression of rapidly dividing cancer cells through the cell cycle has long been pursued as an anticancer strategy. Dobbelstein and Sørensen discuss an alternative approach based on exploiting inherent defects in the DNA replication machinery in cancer cells to promote replicative stress and cell death, and discuss how agents that increase replicative stress might be useful either alone or in combination with conventional chemotherapeutics.

The balance between muscle contraction and relaxation is disrupted in various human diseases, including heart failure, cardiomyopathies, skeletal myopathies and neuromuscular conditions. Here, Hwang and Sykes discuss therapeutic strategies aimed at modulating the mechanical function of the sarcomere, focusing on agents that affect the function of myosin or the troponin complex.

Hydrogen sulfide (H₂S) is a ubiquitous gaseous signalling molecule with a plethora of important roles. In this Review, Wallace and Wang describe the pathways for the synthesis and metabolism of H₂S and its major mechanisms of action in health and in disease processes, before discussing examples of attempts to exploit the actions of H₂S in the design of novel drugs.

The recent growth in the number of academic drug discovery centres is providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To realize the potential of these opportunities, it is important that academic researchers understand the risks in several key areas — including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology — which are discussed in this article.

Hearing loss, which is caused by both genetic and environmental factors, is the most common form of sensory impairment in humans. Current treatment relies on medical devices and there are no drug-based therapies available. Here, Müller and Barr-Gillespie review the various forms of hearing loss, highlight emerging pharmacological targets and discuss the potential of regenerative medicine and gene therapy to restore auditory function.

Dysregulation of mRNA translation is a frequent occurrence in cancer cells, and several components of the translation machinery have emerged as promising targets for anticancer therapeutics. This Review discusses the mechanisms of aberrant mRNA translation in cancer cells and provides an overview of drugs in development that target the translation machinery.

Current influenza vaccines are effective but require reformulation each year and do not protect against pandemic influenza strains. Here, Krammer and Palese discuss the advances in the design and production of seasonal and pandemic influenza virus vaccines, including novel vaccine constructs and adjuvants. Advances in the design of universal influenza vaccines are also presented.

Members of the family of kallikrein (KLK)-related proteases are found in various tissues — including the airway, prostate and brain — and have a wide range of functions. The authors describe the roles of KLKs in health and disease, and highlight the small-molecule, peptide-based, protein-based, antibody-based and immunotherapeutic strategies that are being used to target KLKs in certain diseases.

One strategy for treating cancer while limiting off-target effects on healthy cells is to conjugate cytotoxic agents to small-molecule ligands for receptors that are upregulated in tumours. Low and colleagues explain the key aspects to be considered when designing ligand–drug conjugates, and summarize the ligand–drug and ligand–imaging agent conjugates that are currently in clinical trials.

Components of the cell cycle machinery, such as the cyclin-dependent kinases (CDKs), have long been pursued as anticancer targets. Historically, the development of CDK inhibitors has been challenging, but recent developments, particularly in regard to inhibitors for CDK4 and CDK6, have shown promise. This Review presents an overview of the field and discusses agents in clinical development.

The screening of natural products for lead molecules is an attractive strategy, as most natural products fall within biologically relevant chemical space. In this Review, Harvey, Edrada-Ebel and Quinn discuss how advanced screening, metabolomics and metagenomics approaches can be used in the identification, validation and production of naturally sourced compounds, and highlight examples of naturally derived antimicrobials and inhibitors of protein–protein interactions.