Target validation articles within Nature

Featured

  • Analysis
    | Open Access

    Human genetic evidence increases the success rate of drugs from clinical development to approval but we are still far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

    • Eric Vallabh Minikel
    • , Jeffery L. Painter
    •  & Matthew R. Nelson

  • Article
    | Open Access

    A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.

    • Karanbir S. Pahil
    • , Morgan S. A. Gilman
    •  & Daniel Kahne

  • 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 |

    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 genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets.

    • Benjamin B. Sun
    • , Joseph C. Maranville
    •  & Adam S. Butterworth

  • Letter |

    A selective inhibitor of the kinetoplastid proteasome (GNF6702) is identified that is highly efficacious in vivo, clearing the parasites that cause leishmaniasis, Chagas disease and sleeping sickness from mice, highlighting the possibility of developing a single class of drugs for these neglected diseases.

    • Shilpi Khare
    • , Advait S. Nagle
    •  & Frantisek Supek

  • Letter |

    A small molecule, inhibitor of a protein–protein interaction between the transcription factor Pdr1 and the Med15 subunit of Mediator in the fungal pathogen Candida glabrata, is identified and characterized here; the compound iKIX1 inhibits Pdr1-mediated gene activation and resensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models of disseminated and urinary tract infection.

    • Joy L. Nishikawa
    • , Andras Boeszoermenyi
    •  & Haribabu Arthanari

  • Article |

    A novel drug, ribocil, is shown to mimic the binding of a natural ligand to a bacterial riboflavin riboswitch (a non-coding stretch of messenger RNA whose structure is affected by a ligand—usually one related to the function of the protein encoded by the messenger RNA) to cause inhibition of bacterial growth; the ability to target an RNA structural element with a synthetic small molecule may expand our view of the target space susceptible to therapeutic intervention.

    • John A. Howe
    • , Hao Wang
    •  & Terry Roemer

  • Article |

    This study describes the long-awaited crystal structures for hypoxia-inducible factor (HIF) heterodimers, including complexes bound to small molecules and DNA; the HIF–ARNT architecture is distinct from the bHLH-PAS-containing CLOCK–BMAL1 heterodimer, and HIF mutations linked to cancer can be mapped to important structural regions, with the structures providing future reference for small-molecule drug discovery efforts.

    • Dalei Wu
    • , Nalini Potluri
    •  & Fraydoon Rastinejad

  • Brief Communications Arising |

    • Laurens Kruidenier
    • , Chun-wa Chung
    •  & David M. Wilson

  • Article |

    Quiescent CD4 T cells in lymphoid tissues are shown to die after HIV-1 infection by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death; caspase 1 inhibitors, which are safe for human use, can rescue the cell death in vitro raising the possibility of new therapeutics targeting the host instead of the virus.

    • Gilad Doitsh
    • , Nicole L. K. Galloway
    •  & Warner C. Greene

  • Article |

    The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K.

    • Case W. McNamara
    • , Marcus C. S. Lee
    •  & Elizabeth A. Winzeler

  • Letter |

    The crystal structure of the inner-membrane urea channel HpUreI from Helicobacter pylori, the causative organism of peptic ulcers, reveals how the channel selectively transports urea across the membrane and buffers the pathogen’s periplasmic pH against the acidic gastric environment.

    • David Strugatsky
    • , Reginald McNulty
    •  & Hartmut Luecke

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