Target identification articles within Nature

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  • Article |

    Glucocorticoids reprogram the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and, as a consequence, inhibition of the inflammatory response.

    • Jean-Philippe Auger
    • , Max Zimmermann
    •  & Gerhard Krönke

  • Article
    | Open Access

    A tethered macrocyclic peptide antibiotic class described here—which shows potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii—blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane through inhibition of the LptB2FGC complex.

    • Claudia Zampaloni
    • , Patrizio Mattei
    •  & Kenneth A. Bradley

  • Article |

    A CRISPR–Cas9 screen in a tumour mouse model identifies CD300ld as a tumour receptor on polymorphonuclear myeloid-derived suppressor cells and in vivo experiments indicate that it is a promising target for cancer immunotherapy.

    • Chaoxiong Wang
    • , Xichen Zheng
    •  & Min Luo

  • Review Article |

    This Review provides a perspective on the development of non-cancer therapies based on human genetics studies and suggests measures that can be taken to streamline the pipeline from initial genetic discovery to approved therapy.

    • Katerina Trajanoska
    • , Claude Bhérer
    •  & Vincent Mooser

  • 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 |

    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 |

    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

  • 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 |

    A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.

    • Anatol Luther
    • , Matthias Urfer
    •  & Daniel Obrecht

  • Article |

    Disulfiram is metabolized into copper–diethyldithiocarbamate, which binds to NPL4 and induces its aggregation in cells, leading to blockade of the p97–NPL4–UFD1 pathway and induction of a complex cellular phenotype that results in cell death.

    • Zdenek Skrott
    • , Martin Mistrik
    •  & Jiri Bartek

  • Letter |

    A product of the soluble epoxide hydrolase enzyme, 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP), is implicated in the pathogenesis of diabetic retinopathy; levels of 19,20-DHDP increase in the retinas of mice and humans with diabetes, and inhibition of its production can rescue vascular abnormalities in a mouse model of the disease.

    • Jiong Hu
    • , Sarah Dziumbla
    •  & Ingrid Fleming

  • Letter |

    Fibroblast-specific Il-11 expression causes heart and kidney fibrosis and organ failure, whereas IL-11 inhibition prevents fibroblast activation and organ fibrosis, indicating that IL-11 inhibition is a potential therapeutic strategy to treat fibrotic diseases.

    • Sebastian Schafer
    • , Sivakumar Viswanathan
    •  & Stuart A. Cook

  • Article |

    In vivo CRISPR screening reveals that loss of Ptpn2 increases the response of tumour cells to immunotherapy and increases IFNγ signalling, suggesting that PTPN2 inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response.

    • Robert T. Manguso
    • , Hans W. Pope
    •  & W. Nicholas Haining

  • Letter |

    Both F17-like and type 1 pili promote intestinal colonization in mouse colonic crypts, and the high-affinity mannoside M4284 reduces intestinal colonization of uropathogenic Escherichia coli while simultaneously treating urinary tract infections without disrupting the composition of the gut microbiota.

    • Caitlin N. Spaulding
    • , Roger D. Klein
    •  & Scott J. Hultgren

  • Letter |

    ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth.

    • Michael A. Erb
    • , Thomas G. Scott
    •  & James E. Bradner

  • Article |

    Specific intramolecular interactions of mitofusin 2 amino acid sequences either constrain or permit mitochondrial fusion and the addition of short peptides matching these sequences stabilize the fusion-constrained or fusion-permissive form, thus inhibiting or promoting mitochondrial fusion.

    • Antonietta Franco
    • , Richard N. Kitsis
    •  & Gerald W. Dorn II

  • 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 |

    Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis.

    • Yoko Kojima
    • , Jens-Peter Volkmer
    •  & Nicholas J. Leeper

  • Article |

    This paper reports the identification of a new cereblon-modulating agent, CC-885, which targets the translation termination factor GSPT1 and demonstrates anti-tumour activity in patient-derived tumour cells; the crystal structure of the cereblon–DDB1–GSPT1–CC-885 complex reveals a common motif for cereblon-substrate recruitment.

    • Mary E. Matyskiela
    • , Gang Lu
    •  & Philip P. Chamberlain

  • Letter |

    A small-molecule inhibitor of the Mediator-associated kinases CDK8 and CDK19 inhibits growth of acute myeloid leukaemia (AML) cells and induces upregulation of super-enhancer-associated genes with tumour suppressor and lineage-controlling functions; Mediator kinase inhibition therefore represents a promising therapeutic approach for AML.

    • Henry E. Pelish
    • , Brian B. Liau
    •  & Matthew D. Shair

  • Article |

    The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission.

    • Beatriz Baragaña
    • , Irene Hallyburton
    •  & Ian H. Gilbert

  • Article |

    From a new species of β-proteobacteria, an antibiotic called teixobactin that does not generate resistance has been characterized; the antibiotic has two different lipid targets in different bacterial cell wall synthesis components, which may explain why resistance was not observed.

    • Losee L. Ling
    • , Tanja Schneider
    •  & Kim Lewis

  • Letter |

    Crystal structures of human and prokaryotic ribosomal oxygenases reported here, with and without their ribosomal protein substrates, support their assignments as hydroxylases, and provide insights into the evolution of the JmjC-domain-containing hydroxylases and demethylases.

    • Rasheduzzaman Chowdhury
    • , Rok Sekirnik
    •  & Christopher J. Schofield

  • Letter |

    Nicotinamide N-methyltransferase (NNMT) expression is increased in white adipose tissue and liver of obese and diabetic mice, Nnmt knockdown protects against diet-induced obesity by altering the availability of adipose S-adenosylmethionine and NAD+, rendering Nnmt a novel target for treating obesity and type 2 diabetes.

    • Daniel Kraus
    • , Qin Yang
    •  & Barbara B. Kahn

  • Article |

    A chemoproteomic screen is used here to identify MTH1 as the target of SCH51344, an experimental RAS-dependent cancer drug; a further search for inhibitors revealed (S)-crizotinib as a potent MTH1 antagonist, which suppresses tumour growth in animal models of colon cancer, and could be part of a new class of anticancer drugs.

    • Kilian V. M. Huber
    • , Eidarus Salah
    •  & Giulio Superti-Furga

  • Article |

    RNA-recognition elements are identified for the fragile-X-syndrome-associated RNA-binding protein FMRP, in addition to its target messenger RNAs; although many of FMRP gene targets discovered are involved in brain function and autism spectrum disorder, a proportion are also dysregulated in mouse ovaries, suggesting cross-regulation of signalling pathways in different tissues.

    • Manuel Ascano
    • , Neelanjan Mukherjee
    •  & Thomas Tuschl

  • Letter |

    A cell-autonomous role for the COUP-TFII transcription factor in prostate cancer cells is identified, in which COUP-TFII inhibits TGF-β signalling by binding to SMAD4; COUP-TFII promotes prostate tumorigenesis and metastasis in a mouse model, and is associated with more aggressive disease in human prostate cancers.

    • Jun Qin
    • , San-Pin Wu
    •  & Sophia Y. Tsai

  • Letter |

    A new class of peptides, mambalgins, is isolated from the African snake the black mamba, which can abolish pain through inhibition of particular subtypes of acid-sensing ion channels expressed either in central or peripheral neurons.

    • Sylvie Diochot
    • , Anne Baron
    •  & Eric Lingueglia

  • Letter
    | Open Access

    Exomes, transcriptomes and copy-number alterations in a sample of more than 70 primary human colonic tumours were analysed in an attempt to characterize the genomic landscape; in addition to finding alterations in genes associated with commonly mutated signalling pathways, recurrent gene fusions involving R-spondin family members were also found to occur in approximately 10% of colonic tumours, revealing a potential new therapeutic target.

    • Somasekar Seshagiri
    • , Eric W. Stawiski
    •  & Frederic J. de Sauvage

  • Article |

    A large-scale computational effort is used to predict the activity of 656 drugs against 73 protein targets that have been associated with adverse drug reactions; the abdominal pain side effect of the synthetic oestrogen chlorotrianisene is shown to be mediated through its inhibition of cyclooxygenase-1.

    • Eugen Lounkine
    • , Michael J. Keiser
    •  & Laszlo Urban

  • News & Views |

    Genomic analyses of tumours of the childhood cancer retinoblastoma reveal a low mutation rate, challenging the view that genomic instability is crucial for its progression. The work also identifies a new therapeutic target. See Article p.329

    • Julien Sage
    •  & Michael L. Cleary

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