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Recent studies have indicated the potential to develop small-molecule drugs that act on RNA targets, leading to burgeoning interest in the field. This article discusses general principles for discovering small-molecule drugs that target RNA and argues that the overarching challenge is to identify appropriate target structures in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets.
Co-stimulatory receptors mediate the anticancer immune response. This Review discusses the current efforts in targeting co-stimulatory receptors with agonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
Recent technological advances with cryo-electron microscopy (cryo-EM) — a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies — have raised hopes that it might soon become an important tool for drug discovery, particularly for 'intractable' targets that are still not accessible to analysis by X-ray crystallography. This article describes these advances and critically assesses their relevance for drug discovery.
New therapies in development for haemophilia — including gene therapies, proteins with extended half-lives and inhibitors of natural anticoagulants — look poised to change the management of this disease. In this Review, Peters and Harris discuss recent progress, including the hurdles that still need to be overcome in order to translate these advances into routine clinical use.
Covalent modifications of RNA — mediated by RNA-modifying proteins (RMPs) — affect RNA stability and translation to proteins, and some of these RMPs have been implicated in cancer. Here, Copeland and colleagues review the current understanding of RNA modifications with a focus on mRNA methylation and assess the potential of RMPs as novel anticancer targets.
Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. This Review describes the progress made in recent years in inhibiting IL-6-signalling and analyses the advantages and disadvantages of these approaches.
Prodrug strategies can be used to overcome pharmacokinetic and pharmacodynamic issues in many therapeutic agents. Here, Rautio and colleagues discuss which approaches have been most successful, particularly in the past 10 years, and highlight the challenges in incorporating prodrug moieties during drug development.
Strategies such as diversity-oriented synthesis aim to explore novel areas of chemical space efficiently by populating small-molecule screening libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. This article highlights how the design and synthesis of such libraries have been enabled by modern synthetic chemistry and illustrates the impact of the resultant chemical probes and drug leads in a wide range of diseases.
Existing kinase inhibitor drugs predominantly target receptor tyrosine kinases in cancer. Here, Gray and Ferguson review novel kinase targets in oncology, degenerative diseases, inflammatory disorders and infectious diseases. Advances in medicinal chemistry, selectivity profiling and computer-aided drug design, which are enabling the design of improved kinase inhibitors, are discussed.
Efforts towards developing post-exposure therapies for infections with filoviruses, particularly Ebola and Marburg viruses, increased substantially during the Ebola virus outbreak of 2013–2016. Geisbert and colleagues review the progress made on this front and discuss the challenges and opportunities for developing post-exposure therapies in the future.
In 2011, AstraZeneca set out to improve its research and development (R&D) productivity by focusing decision-making using a framework with five technical determinants: the right target, right tissue, right safety, right patient and right commercial potential. Here, Pangalos and colleagues describe the progress made using this '5R framework', with metrics indicating improved success rates, and discuss where the approach has failed and the lessons learned.
mRNA vaccines represent a promising alternative to conventional vaccine approaches, but their application has been hampered by instability and delivery issues. Here, Pardi and colleagues discuss recent advances in mRNA vaccine technology, assess mRNA vaccines currently in development for cancer and infectious diseases and consider future directions and challenges.
A given G protein-coupled receptor can signal through a range of downstream transducers depending on the stimulating ligand, enabling biased signalling towards different biological outcomes. Lefkowitz and colleagues describe the latest advances in the field, including efforts to harness biased signalling for improved therapeutic outcomes.
