Target identification articles within Nature

Featured

  • Outlook |

    Drugs in development for Alzheimer's disease take aim at a variety of neural mechanisms. But despite a wealth of possibilities, there have been few successes.

    • Lauren Gravitz

  • News & Views |

    The TH17 helper cells of the immune system have a dark side: they mediate autoimmune disorders. Two drugs that prevent the differentiation and activity of these cells might be of therapeutic value. See Letters p.486 & p.491

    • Anton M. Jetten

  • Letter |

    Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful.

    • Trever G. Bivona
    • , Haley Hieronymus
    •  & Charles L. Sawyers

  • Letter |

    Substantial risk for schizophrenia is conferred by large copy number variants at a number of genomic loci. Here, a significant association between duplications on chromosome 7 and schizophrenia is reported. Importantly, microduplication analysis narrowed down the region to a region just upstream of a gene encoding vasoactive intestinal peptide receptor (VIPR2). Increased expression of VIPR2 in patients with schizophrenia implicates VIP signalling as a molecular mechanism underlying schizophrenia.

    • Vladimir Vacic
    • , Shane McCarthy
    •  & Jonathan Sebat

  • News & Views |

    With age comes wisdom, or so they say. The reality is that, with age, the ability to store memories declines. One way of tackling this problem might be to raise neuronal levels of the signalling molecule EphB2. See Article p.47

    • Robert C. Malenka
    •  & Roberto Malinow

  • Letter |

    A major hallmark of Alzheimer's disease is the accumulation in the brain of amyloid-β peptide. This is generated by γ-secretase, which is thus of interest as a target for drugs to prevent amyloid-β accumulation. A problem is that γ-secretase has other substrates, including Notch, important in development. Here, a γ-secretase activating protein is identified that increases amyloid-β production without affecting Notch. Thus this protein can serve as an amyloid-β-lowering drug target without affecting other functions of γ-secretase.

    • Gen He
    • , Wenjie Luo
    •  & Paul Greengard

  • News & Views |

    Presenilin proteins have a major role in normal cellular processes, but some contribute to disease, for example through the formation of amyloid-β. The way in which these different roles are regulated is now becoming clearer.

    • Peter St George-Hyslop
    •  & Gerold Schmitt-Ulms

  • Article |

    Enzymes that move along DNA, such as DNA and RNA polymerases, cause the DNA ahead of them to become supercoiled. This would lead to the DNA becoming overwound, were the stress not relieved by topoisomerases. Topoisomerase inhibitors have been used as antibacterial and anticancer drugs, but the structural basis for their activity has been unclear. Here, the crystal structures are presented of a topoisomerase on DNA, either alone or in the presence of a new type of antibiotic.

    • Benjamin D. Bax
    • , Pan F. Chan
    •  & Michael N. Gwynn

  • Article |

    Here, nearly 2 million compounds from GlaxoSmithKline's chemical library were screened for inhibitors of the malaria parasite Plasmodium falciparum, grown in red blood cells. Of these compounds, some 13,500 inhibited parasite growth, and more than 8,000 also showed potent activity against a multidrug resistant strain. The targets of these compounds were inferred through bioinformatic analysis, revealing several new mechanisms of antimalarial action.

    • Francisco-Javier Gamo
    • , Laura M. Sanz
    •  & Jose F. Garcia-Bustos

  • News & Views |

    Infection with hepatitis C is one of the main causes of liver disease, yet there are no broadly effective treatments. Discovery of a potent inhibitor of this virus shows that researchers must think outside the box.

    • Catherine L. Murray
    •  & Charles M. Rice

  • News |

    The drug stunts limb development in zebrafish and chicks by binding to a protein called cereblon.

    • Janet Fang

  • News & Views |

    Every machine is made of parts. But, as the new structure of the HIV integrase enzyme in complex with viral DNA shows, one could not have predicted from the individual parts just how this machine works.

    • Robert Craigie

  • Letter |

    Sequence variations in a 58-kilobase interval on human chromosome 9p21 have been associated with an increased risk of coronary artery disease. However, this interval contains no protein-coding genes and the mechanism underlying the increased risk has been unclear. Here, the corresponding interval has been deleted from mouse chromosome 4, revealing that this part of the chromosome regulates the cardiac expression of two nearby genes, Cdkn2a and Cdkn2b, and the proliferation dynamics of vascular cells.

    • Axel Visel
    • , Yiwen Zhu
    •  & Len A. Pennacchio

  • Article |

    To survive and evade host responses, malaria parasites export several hundred proteins into the host cell on infection. A feature of these proteins is a conserved, pentameric motif that is cleaved by an unknown protease before export. This is one of two independent studies revealing the identity of the protease as plasmepsin V, an aspartic acid protease located in the endoplasmic reticulum. This enzyme is essential for parasite viability and is an attractive candidate for drug development.

    • Justin A. Boddey
    • , Anthony N. Hodder
    •  & Alan F. Cowman

  • Brief Communications Arising |

    • Sophie Brinster
    • , Gilles Lamberet
    •  & Claire Poyart

  • Letter |

    High mutation rates in the influenza A virus facilitate the generation of viral escape mutants, rendering vaccines and drugs potentially ineffective, but targeting host cell determinants could prevent viral escape. Here, 287 human host cell genes influencing influenza A virus replication are found using a genome-wide RNA interference screen. An independent assay is then used to investigate overlap between genes necessary for different viral strains.

    • Alexander Karlas
    • , Nikolaus Machuy
    •  & Thomas F. Meyer

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