Reviews & Analysis

Physical activity has demonstrated positive effects in preventing and ameliorating a broad range of diseases, particularly central nervous system disorders. Accordingly, strategies to therapeutically mimic the effects of exercise are gaining interest. Here, Gubert and Hannan focus on the molecular and cellular effects of physical activity in the central nervous system, assessing opportunities for the development of therapeutic exercise mimetics.

Despite the rapid growth of the engineered cell therapy sector, there are challenges to the broader industrialization of cells as medicines, especially in the treatment of solid tumours. This Perspective provides an industry perspective on the progress achieved by engineered T cell therapies and discusses strategies to industrialize their potential.

Since the introduction of insulin almost a century ago, more than 80 peptide drugs have been approved for a wide range of diseases. This Perspective summarizes trends in peptide drug discovery, emphasizing lessons from earlier approaches as well as emerging strategies such as integrated venomics and peptide-display libraries. It also analyses the remaining challenges and the pharmaceutical landscape in which peptide drugs are particularly valuable.

Academic research has a key role in identifying new drug targets, but to lead to new drugs this research must progress to testing drug candidates in clinical trials, which are typically conducted by industry. This Perspective presents a framework to support academic scientists and funders in prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical trials.

Phase 0 approaches, including microdosing, evaluate subtherapeutic exposures to novel drugs, potentially enabling safer, cheaper and quicker first-in-human studies. Here, Burt et al. discuss the fundamentals and applications of phase 0 approaches, highlight the potential advantages of their application in drug development and address the associated limitations.

Dendritic cell vaccines have been widely investigated as a type of cancer immunotherapy, but their promise has not yet been realized. Kandalaft and colleagues propose that a prime and boost approach — primed with either standard therapies or dendritic cell vaccines and boosted with a personalized synthetic vaccine — could help fulfil the potential of such vaccines. They discuss improvements in dendritic cell vaccines that have enabled prime–boost approaches, as well as challenges for adoption.

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.

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.

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.

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.

Cells in the innate immune system can display adaptive characteristics that lead to increased responsiveness to secondary stimulation by pathogens. This innate immune memory has been termed ‘trained immunity’. Here, Mulder and colleagues describe the mechanisms responsible for the induction of trained immunity and propose strategies to regulate it as a potential treatment of immune-related diseases.