Drug discovery

  • Article |

    Cryo-electron microscopy structures of the MRGPRX2–Gi1 trimer in complex with polycationic compound 48/80 or inflammatory peptides provide insights into the sensing of cationic allergens by MRGPRX2, potentially facilitating the design of therapies to prevent unwanted pseudoallergic reactions.

    • Fan Yang
    • , Lulu Guo
    •  & Jin-Peng Sun
  • Article |

    MIPS521, a positive allosteric modulator of the adenosine A1 receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.

    • Christopher J. Draper-Joyce
    • , Rebecca Bhola
    •  & Arthur Christopoulos
  • Article |

    An engineered IgM antibody administered intranasally in mice shows high prophylactic efficacy and therapeutic efficacy against SARS-CoV-2, and is also effective against multiple variants of concern that are resistant to IgG-based therapeutics.

    • Zhiqiang Ku
    • , Xuping Xie
    •  & Zhiqiang An
  • Article |

    In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.

    • Kiran Musunuru
    • , Alexandra C. Chadwick
    •  & Sekar Kathiresan
  • Article |

    The bispecific IgG1-like CoV-X2 prevents SARS-CoV-2 spike binding to ACE2, neutralizes SARS-CoV-2 and its variants of concern, protects against disease in a mouse model, whereas the parental monoclonal antibodies generate viral escape.

    • Raoul De Gasparo
    • , Mattia Pedotti
    •  & Luca Varani
  • Article |

    Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

    • Lindsay P. Cameron
    • , Robert J. Tombari
    •  & David E. Olson
  • Article |

    Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

    • Mikołaj Słabicki
    • , Hojong Yoon
    •  & Benjamin L. Ebert
  • Article |

    Genomic integration of an adeno-associated virus vector in a mouse model of Angelman syndrome unsilences paternal Ube3a and rescues anatomical and behavioural phenotypes, suggesting a pathway towards the treatment of this neurodevelopmental disorder.

    • Justin M. Wolter
    • , Hanqian Mao
    •  & Mark J. Zylka
  • Article |

    Results of an exploratory interim analysis from a phase I trial show that an RNA vaccine targeted towards four melanoma-associated antigens produces durable objective responses in patients with melanoma that are accompanied by strong CD4+ and CD8+ T-cell immunity.

    • Ugur Sahin
    • , Petra Oehm
    •  & Özlem Türeci
  • Article |

    A screen of the ReFRAME library of approximately 12,000 known drugs for antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified several candidate compounds with suitable activities and pharmacological profiles, which could potentially expedite the deployment of therapies for coronavirus disease 2019 (COVID-19).

    • Laura Riva
    • , Shuofeng Yuan
    •  & Sumit K. Chanda
  • Article |

    In a mouse model of the leukodystrophy Pelizaeus–Merzbacher disease, myelination, motor performance, respiratory function and lifespan are improved by suppressing proteolipid protein expression, suggesting PLP1 as a therapeutic target for human patients with this disease and, more broadly, antisense oligonucleotides as a pharmaceutical modality for treatment of myelin disorders.

    • Matthew S. Elitt
    • , Lilianne Barbar
    •  & Paul J. Tesar
  • Analysis
    | Open Access

    Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.

    • Eric Vallabh Minikel
    • , Konrad J. Karczewski
    •  & Daniel G. MacArthur
  • Article |

    A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

    • David E. Gordon
    • , Gwendolyn M. Jang
    •  & Nevan J. Krogan
  • Review Article |

    The development and future prospects of prospectively designed multispecific drugs, which have the potential to transform the biopharmaceutical industry by enabling the targeting of currently inaccessible components of the proteome, are reviewed.

    • Raymond J. Deshaies
  • Article |

    VirtualFlow, an open-source drug discovery platform, enables the efficient preparation and virtual screening of ultra-large ligand libraries to identify molecules that bind with high affinity to target proteins.

    • Christoph Gorgulla
    • , Andras Boeszoermenyi
    •  & Haribabu Arthanari
  • Article |

    Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor.

    • Xi Lin
    • , Mingyue Li
    •  & Fei Xu
  • Article |

    A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.

    • Reed M. Stein
    • , Hye Jin Kang
    •  & Margarita L. Dubocovich
  • Article |

    The structure of GLP-1R and its G protein in complex with the small molecule TT-OAD2 sheds light on how the TT-OAD2 agonist can activate the receptor and provides insights into the development of therapeutic agents for metabolic disorders.

    • Peishen Zhao
    • , Yi-Lynn Liang
    •  & Denise Wootten
  • Article |

    The MYST acetyltransferase HBO1 is a critical regulator in maintaining leukaemia stem cells, and a small-molecule inhibitor of HBO1 is developed that shows efficacy against a range of acute myeloid leukaemia cells.

    • Laura MacPherson
    • , Juliana Anokye
    •  & Mark A. Dawson
  • Article |

    Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.

    • Yu Imai
    • , Kirsten J. Meyer
    •  & Kim Lewis
  • Article |

    Compounds that interact with mutant huntingtin and an autophagosomal protein are able to reduce cellular levels of mutant huntingtin by targeting it for autophagic degradation, demonstrating an approach that may have potential for treating proteopathies.

    • Zhaoyang Li
    • , Cen Wang
    •  & Boxun Lu
  • Article |

    High-resolution crystal structures of the rat succinate receptor SUCNR1 in an inactive confirmation, and the humanized rat SUCNR1 bound to an antagonist, provide insights into the structure of these receptors and the species selectivity of antagonist binding.

    • Matthias Haffke
    • , Dominique Fehlmann
    •  & Veli-Pekka Jaakola
  • Article |

    The chimeric cytokine IC7Fc combines the beneficial effects of the cytokines IL-6 and CNTF on weight loss and metabolism in mice, with no obvious side effects in mice and non-human primates.

    • Maria Findeisen
    • , Tamara L. Allen
    •  & Mark A. Febbraio
  • Article |

    Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D4 dopamine receptor with high affinity.

    • Jiankun Lyu
    • , Sheng Wang
    •  & John J. Irwin
  • Article |

    Cryo-electron microscopy structures are reported in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA, and the benzodiazepines alprazolam and diazepam.

    • Simonas Masiulis
    • , Rooma Desai
    •  & A. Radu Aricescu
  • Article |

    Chemical optimization of arylomycins results in an inhibitor of bacterial type I signal peptidase that shows activity both against multidrug-resistant clinical isolates of Gram-negative bacteria in vitro and in several in vivo infection models.

    • Peter A. Smith
    • , Michael F. T. Koehler
    •  & Christopher E. Heise
  • Article |

    Osteoclasts secrete small extracellular vesicles that stimulate osteoblasts, promoting bone formation via receptor activator of nuclear factor-kappa B ligand (RANKL), thereby linking bone formation and resorption.

    • Yuki Ikebuchi
    • , Shigeki Aoki
    •  & Hiroshi Suzuki