Review Articles in 2021

This Review discusses how recent advances in understanding the activation of the innate immune system are shedding light on the immunological mechanisms of action of adjuvants and highlights how systems-based approaches are beginning to revitalize adjuvant design and development.

Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Here, Crooke and colleagues describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of antisense oligonucleotides in a wide range of therapeutic applications.

Protein arginine methyltransferases (PRMTs) regulate numerous biological processes, including transcription, splicing and the DNA damage response. In this article, Barsyte-Lovejoy and colleagues discuss the development of PRMT inhibitors, predominantly for cancer, and describe the challenges and potential new indications in which PRMT inhibition could be therapeutically relevant.

Gasdermins (GSDMs) are a recently characterized protein family that mediate a programmed inflammatory cell death termed pyroptosis. Here, Lieberman and colleagues review current understanding of the expression, activation and regulation of GSDMs, highlighting their roles in cell death, cytokine secretion and inflammation. Emerging opportunities to develop GSDM-targeted drugs and the associated challenges are highlighted.

Although checkpoint inhibitor blockade has been extremely successful in certain types of cancer, harnessing the immune system for immunosurveillance has met with numerous failures. In this Review, Mak and colleagues discuss the lessons learned from these failures, and how to incorporate the growing understanding of immuno-oncology into potential therapies, including combinations with existing checkpoint inhibitors.

The blood–brain barrier is a perennial challenge for the delivery of therapeutics to the central nervous system. In their Review, Terstappen and colleagues discuss non-invasive approaches to brain delivery, particularly for biopharmaceuticals, some of which are now in clinical testing.

Disregulation of circadian rhythms, as a result of jet lag or other lifestyle factors, can increase the risks of certain diseases. This Review analyses the different pathways involved in the regulation of the circadian clock and strategies that target the circadian systems.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

Protein lysine methylation is an important post-translational modification of histone and non-histone proteins. In this Review, Gozani and colleagues discuss the role of protein lysine methyltransferases, the ‘writers’ of protein lysine methylation, in a range of diseases, and the progress and potential of targeting these enzymes therapeutically. They also consider the biology of lysine methyltransferases beyond epigenetic regulation as emerging targets for drug discovery.

Numerous proteins and lipids are covered in glycans, which affects the way these molecules interact. In this Review, Smith and Bertozzi discuss therapies targeting proteins that recognize glycosylation, namely the selectins and Siglecs, as well as glycan-targeted antibodies that have entered the clinic or are in development. They provide their perspectives on the future of glycobiology.