Review Articles

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.

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.

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.

Galectins are glycan-binding proteins with broad roles in physiological and pathological processes. Here, Rabinovich and colleagues discuss the therapeutic relevance of galectins to cancer and fibrosis and review the various strategies to target galectins and their progress in clinical trials.

Dysregulated protein phosphorylation is implicated in numerous human diseases, but targeting protein phosphates has traditionally proved challenging. Here, Stanford and Bottini provide an overview of protein phosphatase families, focusing on their roles in autoimmunity and tumour immunity. Emerging strategies to tackle these targets and agents in development are assessed.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons. In their Review, Shaw and colleagues provide a comprehensive picture of the various pathological mechanisms involved in this complex disease, and discuss the deep and diverse pipeline under development to tackle these processes. They highlight advances in ALS translational research that might be broadly applicable to other neurodegenerative disorders.

Single-agent therapies targeting specific dysregulated pathways in cancer can be highly effective, but drug resistance frequently develops. Here, Bernards and colleagues discuss the mechanisms underlying resistance to targeted therapies, and assess how these can be suppressed by using tailored combination therapies.

The potential of therapeutically targeting phosphoinositide kinases (PIKs) beyond the class I PI3Ks is increasingly being realized. Here, Burke et al. describe the structure, function, regulation and roles in disease of all clinically relevant PIKs outside of the class I PI3Ks, assessing potent and specific small-molecule inhibitors in development.

The discovery of the monoclonal antibody trastuzumab almost 25 years ago revolutionized treatment and drug development for HER2⁺ breast cancer. Here, Swain et al. review the current standard of care for HER2⁺ breast cancer, describe mechanisms of drug resistance and focus on next-generation platforms and therapies for the treatment of this disease.