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

Advances in computational omics technologies are enabling access to the hidden diversity of natural products, and artificial intelligence approaches are facilitating key steps in harnessing the therapeutic potential of such compounds, including biological activity prediction. This article discusses synergies between these fields to effectively identify drug candidates from the plethora of molecules produced by nature, and how to address the challenges in realizing the potential of these synergies.

In vivo gene supplementation using adeno-associated virus (AAV) vectors holds substantial promise for a range of neurological disorders. In this Review, the authors discuss ongoing clinical trials and growing knowledge on factors that affect translational success and safety. They outline approaches to increase efficacy and reduce potential toxicity, including optimization of the AAV vector, and consider new frontiers and unmet needs in the field.

Malaria case numbers are rising globally and there is a vital need for new medicines that overcome the emergence of drug resistance. This Review describes the current landscape of small-molecule antimalarial therapies and the methods used to discover them as well as perspectives on approaches to find new targets and treatments.

Duchenne muscular dystrophy is an inherited muscle-wasting disease caused by mutations that disrupt production of dystrophin protein. This Review discusses the plethora of therapeutic approaches being developed to restore dystrophin function, such as exon skipping, gene replacement, cell therapy and gene editing, and highlights recent clinical approvals.

Several forms of non-apoptotic cell death, such as necroptosis, pyroptosis, parthanatos and ferroptosis, are implicated in degenerative diseases, cancer and inflammation. This article describes the molecular pathways regulating these forms of cell death and gives an update on small-molecule inhibitors being developed to target these pathways.

Cytokines mediate a broad range of cellular functions, and the regulation of their activity is important both physiologically and pathologically. This Review explores the biology, signalling and regulation of cytokines and their receptors. Focusing on IL-2, engineering strategies and agents aimed at therapeutically redirecting and fine-tuning cytokine actions, particularly for applications in cancer and autoimmune disease, are assessed.

Increased understanding of the molecular mechanisms underlying type 2 chronic inflammatory diseases has facilitated the development of more targeted therapies for these conditions. Focusing on five major type 2 diseases, this Review provides an overview of the pathogenic drivers of type 2 inflammation, assesses agents that target them and considers emerging novel therapies and unmet needs.

Current treatments for the two most common chronic inflammatory skin disorders, atopic dermatitis and psoriasis, are mainly limited to the alleviation of symptoms. Here, Bieber discusses opportunities and strategies for the discovery and development of interventions aimed at inducing remission of these disorders and their associated comorbidities, assessing key issues that must be addressed to reach this goal.

Cancer therapy has changed substantially since the beginning of the century, with advances including kinase inhibitors and immunotherapies resulting in substantial improvements in treatment outcomes. This Review summarizes trends in the approval of oncology therapeutic products by the FDA since 2000 and discusses the implications for the future of anticancer drug development.

DNA-encoded library (DEL) technology is a powerful small-molecule discovery platform, offering many advantages over traditional screening methods. Here, Peterson and Liu provide an in-depth review of recent small molecules discovered through DELs, illustrating the versatility, efficiency and broad impact of this technology.

Antibody–drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of cytotoxic agents. The technology to develop these agents has improved in past years, but toxicity remains a key issue. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.

Substituting a hydrogen atom with its heavy isotope deuterium may improve the pharmacokinetic and/or toxicity profile of a drug compared with its non-deuterated counterpart. This article highlights milestones in the field of deuteration in drug discovery and development, and discusses recent examples of its application, which have shifted towards deuteration of novel drug candidates instead of developing deuterated analogues of marketed drugs.

Many diseases involve reduced or absent levels of a particular protein and would benefit from therapies that increase gene expression. In their Review, Khorkova et al. discuss the growing range of RNA-targeted therapies in development that aim to boost gene expression, including nucleic acid-based therapeutics targeting the complex regulatory network of non-coding RNA species.

The COVID-19 pandemic spurred a wave of rapid and collaborative drug discovery efforts. This Perspective article summarizes scientific drivers and considerations behind such antiviral small-molecule discovery programmes and proposes strategies to accelerate future efforts.

There have been significant recent advances in the development of single-cell technologies, providing remarkable opportunities for drug discovery and development. Here, Ferran and colleagues discuss how single-cell technologies, primarily single-cell RNA sequencing methods, are being applied in the drug discovery pipeline, from target identification to clinical decision-making. Ongoing challenges and potential future directions are discussed.

Since the COVID-19 pandemic began, many potential therapeutics that target SARS-CoV-2 and/or human proteins to control viral infection have been investigated, with a few receiving authorization by regulatory agencies. This Review article summarizes progress with COVID-19 drug discovery, and discusses the lessons learned about aspects such as drug repurposing, disease models and clinical development strategies.

Drugs that target angiogenic factors such as vascular endothelial growth factor (VEGF) are approved for clinical use in oncology and ophthalmology, but challenges remain. Cao et al. discuss strategies to enhance therapeutic efficacy, overcome drug resistance, define biomarkers and develop next-generation agents for other diseases.

Improving medication adherence is recognized as one of the most impactful and cost-effective strategies for improving the health of the general population. Here, Baryakova and colleagues assess the potential of next-generation drug delivery systems to mitigate many common impediments to adherence and discuss the impact that drug delivery systems have had across different disease types.

Bivalent protein degraders such as proteolysis targeting chimeras (PROTACs) are entering clinical trials, with a current focus on oral administration. O’Brien Laramy et al. propose that implementing non-oral drug delivery technologies guided by pharmacokinetic–pharmacodynamic modelling could expand the chemical design space for degraders as well as the number of druggable targets.

Bayesian statistical approaches that explicitly incorporate existing data into clinical trial design, analysis and decision-making have the potential to substantially reduce the time and cost of bringing new medicines to patients in some contexts, but remain underused. This Perspective highlights the value of Bayesian methods in drug development, discusses barriers to their application and recommends approaches to address them.