Perspectives in 2021

This Perspective on cancer immunotherapy marks the tenth anniversary of the approval of the first immune checkpoint blockade (ICB) drug, ipilimumab, revisiting the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.

Targeted protein degradation by proteolysis-targeting chimeras (PROTACs) is attracting substantial interest as a therapeutic modality that could circumvent some limitations of traditional small-molecule drugs. This article presents a systematic approach to assessing the PROTAC tractability (PROTACtability) of protein targets, which could support decision-making on whether a particular target may be amenable to modulation using a PROTAC.

A substantial proportion of drug targets are embedded in a cellular membrane, and growing evidence shows that some small molecules access their target via a membrane pathway. Here, Payandeh and Volgraf consider the importance of drug binding at the protein–phospholipid interface, and suggest strategies to harness these concepts for improved drug design.

Over the past decade, several RNA-based therapies have gained FDA approval. Additional noncoding RNA (ncRNA)-based therapeutic approaches — targeting microRNAs and long ncRNAs — are now also gaining interest. Here, Calin and co-authors assess the hurdles facing the clinical translation of ncRNA-based therapeutics and highlight promising emerging solutions to address these issues.

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.