Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review

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  • 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.

    • Cedrik M. Britten
    • Aiman Shalabi
    • Axel Hoos
  • 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.

    • Bali Pulendran
    • Prabhu S. Arunachalam
    • Derek T. O’Hagan
    Review Article
  • 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.

    • Stanley T. Crooke
    • Brenda F. Baker
    • Xue-hai Liang
    Review Article
  • 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.

    • Qin Wu
    • Matthieu Schapira
    • Dalia Barsyte-Lovejoy
    Review Article
  • 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.

    • Xing Liu
    • Shiyu Xia
    • Judy Lieberman
    Review Article
  • 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.

    • Shawn P. Kubli
    • Thorsten Berger
    • Tak W. Mak
    Review Article
  • 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.

    • Georg C. Terstappen
    • Axel H. Meyer
    • Wandong Zhang
    Review Article
  • 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.

    • Wei Ruan
    • Xiaoyi Yuan
    • Holger K. Eltzschig
    Review Article
  • 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.

    • Markus Muttenthaler
    • Glenn F. King
    • Paul F. Alewood
  • 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.

    • Atanas G. Atanasov
    • Sergey B. Zotchev
    • Claudiu T. Supuran
    Review Article
  • 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.

    • Kamakoti P. Bhat
    • H. Ümit Kaniskan
    • Or Gozani
    Review Article
  • 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.

    • Benjamin A. H. Smith
    • Carolyn R. Bertozzi
    Review Article
  • Image-based profiling is a strategy to mine the rich information in biological images. Carpenter and colleagues discuss how the application of machine learning is renewing interest in image-based profiling for all aspects of the drug discovery process, from understanding disease mechanisms to predicting a drug’s activity or mechanism of action.

    • Srinivas Niranj Chandrasekaran
    • Hugo Ceulemans
    • Anne E. Carpenter
    Review Article
  • Examining B cell depletion therapy (BCDT), an approved treatment for B cell malignancies, in autoimmune conditions has provided key insights into basic B cell biology. In this Review, Gommerman and colleagues discuss BCDT in autoimmune conditions, highlighting diseases in which BCDT has been clinically effective and the potential and pitfalls for BCDT in autoimmune conditions in which it has not yet been efficacious.

    • Dennis S. W. Lee
    • Olga L. Rojas
    • Jennifer L. Gommerman
    Review Article
  • The Notch pathway plays multiple complex roles in cancer, exerting oncogenic or tumour-suppressive actions depending on the context. Here Miele and colleagues provide an overview of current understanding of the functions of Notch in cancer, highlighting key implications for the development of Notch-targeting therapeutics. Agents in clinical development and emerging therapeutic strategies are highlighted.

    • Samarpan Majumder
    • Judy S. Crabtree
    • Lucio Miele
    Review Article
  • Advances in nanoparticle design could make substantial contributions to personalized and non-personalized medicine. In this Review, Langer, Mitchell, Peppas and colleagues discuss advances in nanoparticle design that overcome heterogeneous barriers to delivery, as well as the challenges in translating these design improvements into personalized medicine approaches.

    • Michael J. Mitchell
    • Margaret M. Billingsley
    • Robert Langer
    Review Article
  • 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.

    • Christoph H. Emmerich
    • Lorena Martinez Gamboa
    • Michael J. Parnham
  • Targeting protein complexes, including those containing G protein-coupled receptors or ligand-gated ion channels, could provide opportunities to increase the target and functional selectivity of novel drugs compared with existing therapies, which only target the receptors. This Review discusses the landscape of ligand-gated ion channel and G protein-coupled receptor complexes as therapeutic targets, as well as strategies for their pharmacological modulation.

    • Mette Ishøy Rosenbaum
    • Louise S. Clemmensen
    • Kristian Strømgaard
    Review Article
  • FOXO proteins are transcription factors that regulate responses to stress stimuli to maintain cellular homeostasis. The deregulation of FOXO protein functions plays a role in cardiovascular disease, cancer, diabetes and neurological diseases. This Review summarizes the biology of FOXO proteins and their functions in disease and longevity and discusses the pharmacological approaches to develop FOXO-targeting therapeutics.

    • Giampaolo Calissi
    • Eric W.-F. Lam
    • Wolfgang Link
    Review Article
  • Base editing is emerging as a potential approach to treat genetic diseases through the introduction of single-nucleotide alterations in DNA and RNA. Here, Porto et al. provide an overview of DNA and RNA base editing, discuss recent advances in the development of these technologies and highlight promising therapeutic applications.

    • Elizabeth M. Porto
    • Alexis C. Komor
    • Gene W. Yeo
    Review Article