Drug discovery

  • Article |

    Inhibiting the asialoglycoprotein receptor ASGR1 increases cholesterol excretion to the bile and then faeces, providing a unique way to lower cholesterol, and therefore providing a safe and effective way to treat cardiovascular disease.

    • Ju-Qiong Wang
    • , Liang-Liang Li
    •  & Bao-Liang Song
  • Article
    | Open Access

    Cryo-electron microscopy structure, molecular dynamics and biochemical analyses of the SHOC2–PP1C–MRAS complex demonstrate the dependence of the complex formation on RAS–GTP and identify the determinants of RAS isoform preference for SHOC2–PP1C and specificity of the complex for RAF dephosphorylation.

    • Nicholas P. D. Liau
    • , Matthew C. Johnson
    •  & Jawahar Sudhamsu
  • Article
    | Open Access

    Cryo-electron structures of the hepatitis B virus receptor NTCP show a distinct membrane topology compared with other SLC10 proteins, but a common bile acid transport mechanism that is shared with related mammalian and bacterial proteins.

    • Jae-Hyun Park
    • , Masashi Iwamoto
    •  & Sam-Yong Park
  • Article |

    A synthetic route to GB18, an alkaloid from the bark of hallucinogenic Galbulimima sp., is developed, enabling its identification as an antagonist of κ- and μ-opioid receptors.

    • Stone Woo
    •  & Ryan A. Shenvi
  • Article
    | Open Access

    A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.

    • Tirosh Shapira
    • , I. Abrrey Monreal
    •  & François Jean
  • Article
    | Open Access

    A survey of potency and efficacy of 2,025 clinically relevant two-drug combinations against 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines identifies rare synergistic effects of anticancer drugs, informing rational combination treatments for specific cancer subtypes.

    • Patricia Jaaks
    • , Elizabeth A. Coker
    •  & Mathew J. Garnett
  • Article |

    V-SYNTHES, a scalable and computationally cost-effective synthon-based approach to compound screening, identified compounds with a high affinity for CB2 and CB1 in a hierarchical structure-based screen of more than 11 billion compounds.

    • Arman A. Sadybekov
    • , Anastasiia V. Sadybekov
    •  & Vsevolod Katritch
  • 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