Reviews & Analysis

Oral delivery of peptide therapeutics could have benefits for treatment adherence, but it faces barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies to overcome these barriers and discusses experience with oral peptides that have reached clinical trials, including the recent landmark approval of an oral formulation of semaglutide for the treatment of type 2 diabetes.

Most rare diseases still lack approved treatments. This article analyses the main therapeutic modalities available to researchers interested in translating advances in the scientific understanding of rare diseases into therapies, highlights progress so far and discusses overarching issues in drug development for rare diseases.

Artificial intelligence (AI) tools are increasingly being applied in drug discovery. This article presents the views of a group of international experts on the ‘grand challenges’ in small-molecule drug discovery with AI, including obtaining appropriate data sets, generating new hypotheses, optimizing in a multi-objective manner, reducing cycle times and changing the research culture.

Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.

Genomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.

Small molecules that induce targeted protein degradation by the ubiquitin–proteasome system, such as proteolysis-targeting chimeras (PROTACs), are attracting great interest as a new therapeutic modality. This Perspective discusses opportunities and challenges for expanding the applicability of targeted protein degradation, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.

Cell plasticity has emerged as a mode of targeted therapy evasion in various cancers. This Review discusses the different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them in order to achieve more durable clinical responses.

Precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer.

Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.

Fibrosis features in numerous chronic diseases, such as non-alcoholic steatohepatitis and heart failure, and no existing therapies can prevent or reverse this abnormal deposition of extracellular matrix, which leads to organ dysfunction. Here, Liu and colleagues describe how this energy-intensive process could be targeted by therapies that interfere with metabolism, including the metabolic implications of drugs directed at transforming growth factor-β and the deposition of extracellular matrix.

Our increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results. This Review describes the key advances and prospects in designing and implementing regulatory T cells as multifaceted, adaptable smart therapeutics in autoimmunity and transplantation.

γδT cells display potent cytotoxicity towards a large array of haematological and solid tumours while preserving normal tissues. In this Review, Sebestyen et al. analyse the tumour specificity mechanisms of γδT cells and the challenges and opportunities for the use of such cells and their receptors in cancer immunotherapy.

Defective lysosomal function has been implicated in diseases ranging from rare lysosomal storage disorders to more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. Here, Muller and colleagues provide an overview of the physiological and pathological roles of lysosomes and assess the progress and opportunities for therapeutically targeting lysosomal proteins and processes.

Adaptive platform trials, which can study multiple therapeutic interventions in a disease in a perpetual manner, offer the potential to improve the efficiency of drug development. This article reviews common features and issues that arise with such trials, and puts forward recommendations to promote best practices in their design, conduct, oversight and reporting.

Adhesion G protein-coupled receptors (aGPCRs) have been linked to multiple diseases, but no therapeutics targeting this GPCR family are yet in clinical trials, in part because a lack of understanding of the atypical features of aGPCRs has hampered the development of molecules targeting them. In this Perspective, Bassilana and colleagues discuss how recent advances in aGPCR biology could provide the basis for a framework to approach the unique challenges of drug discovery programmes targeting these receptors.

Drug development for treatment of hepatitis B virus infection has trailed behind that for infection with the related hepatitis C virus, but encouraging progress has been made in recent years. Fanning and colleagues review advances in hepatitis B therapies and challenges for their development, including antiviral and immune-boosting strategies that could be part of combination strategies to achieve functional cure.

The pathophysiological complexity of progressive multiple sclerosis (MS) challenges the development of effective treatments, despite the substantial unmet clinical need. In this Review, Faissner, Yong and colleagues highlight the need for therapies that target inflammation, neurodegeneration and remyelination, which will likely be needed in combination. The setbacks encountered so far and future challenges are also discussed.

Cyclic nucleotide phosphodiesterases (PDEs) have roles in numerous biological processes and their dysfunction has been associated with various diseases including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Here, Kelly and colleagues assess the current status of therapeutic PDE inhibitors, and highlight emerging novel strategies to therapeutically target PDE function.

Metabolic reprogramming alters immune cell activation, differentiation and function. Powell and colleagues discuss how to specifically modulate the activity of immune cells by altering their metabolism, suggesting a model of ‘cellular selectivity based on demand’, and highlight the opportunities to therapeutically target immunometabolism in cancer and autoimmune disorders.

The complement system has a pivotal role in immunosurveillance and its dysregulation is involved in a variety of diseases. Here, Lambris and colleagues provide an overview of the pathological roles of the complement system in acute and chronic disorders, assessing recent developments in complement drug discovery, while highlighting the associated opportunities and challenges.