Reviews & Analysis

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  • Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.

    • Christian Klein
    • Ulrich Brinkmann
    • Roland E. Kontermann
    Review Article
  • Treatments for tuberculosis have markedly improved in recent years, but lung disease caused by nontuberculous mycobacteria (NTM) is on the rise and lacks effective cures. This Review discusses promising small-molecule drug candidates and innovative clinical trial designs and highlights how lessons from tuberculosis therapeutic development can be applied to NTM disease.

    • Véronique Dartois
    • Thomas Dick
    Review Article
  • Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.

    • Aleksandra Galetin
    • Kim L. R. Brouwer
    • Kathleen M. Giacomini
    Review Article
  • The field of nucleic acid therapeutics is rapidly expanding, with mRNA drug and vaccine candidates now under development for diverse indications. However, various safety concerns are associated with the mRNA platform. This Review discusses key challenges and toxicities identified during the development of mRNA drugs and vaccines, assesses models and tools used to limit toxicity, highlighting knowledge gaps and future directions.

    • Dimitrios Bitounis
    • Eric Jacquinet
    • Mansoor M. Amiji
    Review Article
  • This Review discusses the mechanisms that regulate stabilization of hypoxia-inducible factors (HIFs), and the pharmacological strategies to activate or inhibit HIFs in diseases such as ischaemia, inflammation, cancer, retinal neovascularization and pulmonary hypertension.

    • Xiaoyi Yuan
    • Wei Ruan
    • Holger K. Eltzschig
    Review Article
  • Several challenges hamper the translation of preclinical drug discovery efforts into safe and effective therapies for psychiatric disorders. In their Perspective, Khodosevich and colleagues highlight differences between drug targets in animal models and those in patients as a key reason for failed clinical studies. They present a framework that integrates single-cell and spatial omics data to overcome this loss in translation, which they hope will assist the development of new drugs for diseases such as schizophrenia and major depressive disorder.

    • Konstantin Khodosevich
    • Katarina Dragicevic
    • Oliver Howes
    Perspective
  • The TAM tyrosine kinase receptors TYRO3, AXL and MERTK regulate tissue and immune homeostasis. This Review discusses how their aberrant signalling is linked to diseases such as cancer, fibrosis and viral infection, and surveys the therapeutic landscape of TAM receptor inhibitors in preclinical and clinical development.

    • Yu Rebecca Miao
    • Erinn B. Rankin
    • Amato J. Giaccia
    Review Article
  • Advances with deep learning, the growth of databases of molecules for virtual screening and improvements in computational power have supported the emergence of a new field of quantitative structure–activity relationship (QSAR) modelling applications that Tropsha et al. term ‘deep QSAR’. This article discusses key advances in the field, including deep generative and reinforcement learning approaches in molecular design, deep learning models for synthetic planning, and the use of deep QSAR models in structure-based virtual screening.

    • Alexander Tropsha
    • Olexandr Isayev
    • Artem Cherkasov
    Perspective
  • A diverse range of systems have recently been developed to promote the degradation of extracellular and membrane protein targets by using bispecific antibodies, conjugates or small molecules to traffic targeted proteins to the lysosome. This article describes and categorizes systems for extracellular targeted protein degradation, including LYTACs, ATACs, AbTACs, PROTABs and KineTACs, and discusses their advantages and the challenges ahead to realizing their therapeutic potential.

    • James A. Wells
    • Kaan Kumru
    Review Article
  • The potential of harnessing tRNAs to treat genetic diseases has recently gained significant attention. Here, Coller and Ignatova provide an overview of the history and potential applications of tRNA-based therapies, summarize advances in tRNA cargo design and delivery strategies, and assess the challenges encountered in establishing tRNAs as effective and safe therapeutics.

    • Jeff Coller
    • Zoya Ignatova
    Review Article
  • Inflammasomes are central instigators of the inflammatory response to infection and tissue damage and key regulators in diverse diseases. Here, the authors describe signalling mechanisms that regulate the NLRP3 inflammasome pathways and recent progress in the development of inhibitors and agonists that are advancing into the clinic.

    • Lieselotte Vande Walle
    • Mohamed Lamkanfi
    Review Article
  • The recent success of mRNA vaccines has boosted the prospects for the development of a new class of designer medicines based on mRNA. This Review discusses the multiple design parameters that need to be carefully considered to create highly effective mRNA medicines.

    • Mihir Metkar
    • Christopher S. Pepin
    • Melissa J. Moore
    Review Article
  • Synapses are crucial nodes for communication between neurons and are frequently damaged or dysfunctional in a range of neurodegenerative diseases. In their Review, Dejanovic, Sheng and Hanson outline the current understanding of pathological mechanisms operating at the synapse. They discuss several synapse-targeted approaches in preclinical and clinical development, which could be particularly valuable in combination with other therapeutic strategies.

    • Borislav Dejanovic
    • Morgan Sheng
    • Jesse E. Hanson
    Review Article
  • T cell receptors (TCRs) enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. This Review discusses the current cancer treatment landscape using TCRs and TCR-like molecules, including adoptive cell transfer of T cells expressing endogenous or engineered TCRs or TCR bispecific engagers.

    • Christopher A. Klebanoff
    • Smita S. Chandran
    • Antoni Ribas
    Review Article
  • New classes of antibiotic with activity against Gram-negative bacteria that are resistant to existing drugs are urgently needed, but have been very challenging to identify. This Review describes promising but as-yet-unrealized targets for antibacterial drugs against Gram-negative bacteria and highlights lessons learned from past drug discovery programmes.

    • Ursula Theuretzbacher
    • Benjamin Blasco
    • Laura J. V. Piddock
    Review Article
  • CRISPR-based genome editing has the potential to treat many human genetic diseases, but achieving stable, efficient and safe in vivo delivery remains a challenge. This Review assesses current delivery systems for genome editors—focusing on adeno-associated viruses and lipid nanoparticles—and highlights data from recent clinical trials. Emerging delivery systems and ongoing challenges in the field are discussed.

    • Victoria Madigan
    • Feng Zhang
    • James E. Dahlman
    Review Article
  • Advances in computational omics technologies are enabling access to the hidden diversity of natural products, and artificial intelligence approaches are facilitating key steps in harnessing the therapeutic potential of such compounds, including biological activity prediction. This article discusses synergies between these fields to effectively identify drug candidates from the plethora of molecules produced by nature, and how to address the challenges in realizing the potential of these synergies.

    • Michael W. Mullowney
    • Katherine R. Duncan
    • Marnix H. Medema
    Review Article
  • In vivo gene supplementation using adeno-associated virus (AAV) vectors holds substantial promise for a range of neurological disorders. In this Review, the authors discuss ongoing clinical trials and growing knowledge on factors that affect translational success and safety. They outline approaches to increase efficacy and reduce potential toxicity, including optimization of the AAV vector, and consider new frontiers and unmet needs in the field.

    • Qinglan Ling
    • Jessica A. Herstine
    • Steven J. Gray
    Review Article
  • Malaria case numbers are rising globally and there is a vital need for new medicines that overcome the emergence of drug resistance. This Review describes the current landscape of small-molecule antimalarial therapies and the methods used to discover them as well as perspectives on approaches to find new targets and treatments.

    • Jair L. Siqueira-Neto
    • Kathryn J. Wicht
    • Elizabeth A. Winzeler
    Review Article