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  • The rational discovery of covalent drugs depends on an expanding toolset of techniques. Here, Daniel Nomura and colleagues highlight covalent drugs that have achieved success over the past decade and discuss the tools and strategies that facilitate their discovery, describing two complementary approaches, namely, ligand-first and electrophile-first strategies.

    • Lydia Boike
    • Nathaniel J. Henning
    • Daniel K. Nomura
    Review Article
  • A decade on from the launch of the pioneering autism biomarker discovery initiative EU-AIMS, here we highlight advances in biomarker discovery and validation from the follow-on AIMS-2-TRIALS programme, which aims to improve the wellbeing and outcomes of autistic people through precision healthcare approaches.

    • Bethany F. M. Oakley
    • Eva Loth
    • Declan G. Murphy
  • Peptide and protein drugs have proven successful in the treatment of a wide range of diseases, but their use can be limited by their inherent short-life and need for parenteral administration. Here, Kurtzhals et al. discuss how fatty acid derivatization can be applied to address these issues and optimize the pharmacological properties of peptide and protein drugs, highlighting associated considerations and future directions.

    • Peter Kurtzhals
    • Søren Østergaard
    • Thomas Kjeldsen
    Review Article
  • This Review provides an update on the application of small-molecule drugs in immuno-oncology, discussing current development of small molecules designed to stimulate the antitumour immune response directly and indirectly, and the rapidly increasing efforts towards the discovery of small molecules that target T cell checkpoints.

    • Rienk Offringa
    • Lisa Kötzner
    • Klaus Urbahns
    Review Article
  • Macrophages can promote tumorigenesis and enhance the antitumour response. This Review discusses the molecular mechanisms underlying the reprogramming of macrophages in the tumour microenvironment and provides an overview of macrophage-targeted therapies for the treatment of cancer.

    • Alberto Mantovani
    • Paola Allavena
    • Cecilia Garlanda
    Review Article
  • Emerging understanding of biomolecular condensates — transient liquid-like droplets made up of proteins and nucleic acids — in normal and aberrant cellular states is providing new insights into human diseases. This Perspective proposes that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics, and discusses the strategies, techniques and challenges involved.

    • Diana M. Mitrea
    • Matthäus Mittasch
    • Mark A. Murcko
  • INCATE, the INCubator for Antibacterial Therapies in Europe, aims to boost the antibiotic pipeline by accelerating the translation of academic innovation into industrial R&D projects to tackle antimicrobial resistance. Founded in 2021 as a partnership of research institutions and pharma companies, INCATE provides advice, community and non-dilutive funding to start-up companies.

    • Silke Alt
    • Douglas Haggstrom
    • Christoph Dehio
  • The UK Biobank houses an extensive collection of biological samples and health information from 500,000 volunteers, providing clues to the genetic and environmental drivers of disease. Naomi Allen, the project’s chief scientist and an epidemiologist at Oxford University, discusses the exploding body of findings from this 20-year-old biomedical resource and the prospects for the expansion of this biopharmaceutical treasure trove.

    • Asher Mullard
    An Audience With
  • Evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown in the past decade. Nedergaard and colleagues overview the evidence for the glymphatic system and its role in disease, and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

    • Terhi J. Lohela
    • Tuomas O. Lilius
    • Maiken Nedergaard
  • The potential of therapeutically targeting RNA structures with small molecules is being increasingly recognized. Here, Disney and colleagues review strategies to identify, validate and optimize small-molecule RNA binders. Examples of existing RNA-targeted small molecules, as well as challenges and future directions in the field, are discussed.

    • Jessica L. Childs-Disney
    • Xueyi Yang
    • Matthew D. Disney
    Review Article