Correspondence |
Featured
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Feature |
Pharmaceutical sector: Delicate transition
With lay-offs rife in the drug industry, life scientists and chemists are seeking fresh career paths.
- Charlotte Schubert
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News & Views |
Computer model predicts side effects
Drug candidates are usually found to be unsafe only late in the drug discovery process. A method for predicting the many biological targets of a given molecule might allow drug safety to be considered much earlier. See Article p.361
- Kyle Kolaja
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Article |
Large-scale prediction and testing of drug activity on side-effect targets
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
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News & Views |
A breach in the blood–brain barrier
Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development. See Letter p.512
- Peter Carmeliet
- & Bart De Strooper
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Letter |
Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic
The crystal structure of the human nociceptin/orphanin FQ peptide receptor in complex with the peptide mimetic antagonist compound-24 is determined, with potential importance for the development of new therapeutic agents.
- Aaron A. Thompson
- , Wei Liu
- & Raymond C. Stevens
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Letter |
Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’
Although IL-2 has been studied for its immune-stimulating activity against metastatic cancer, its side effects have limited its clinical use; here, an engineered IL-2 ‘superkine’ is shown to have increased activity, particularly in inducing antitumour T cells, but fewer side effects.
- Aron M. Levin
- , Darren L. Bates
- & K. Christopher Garcia
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Article |
Crystal structure of the µ-opioid receptor bound to a morphinan antagonist
The crystal structure of the mouse μ-opioid receptor bound to an antagonist is described, with possible implications for the future development of analgesics.
- Aashish Manglik
- , Andrew C. Kruse
- & Sébastien Granier
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News |
How marijuana makes you forget
Drug affects previously overlooked brain cells that have a crucial role in memory formation.
- Mo Costandi
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News |
Drug bests cystic-fibrosis mutation
First treatment to tackle protein behind the disease wins approval — but only a small fraction of patients will benefit.
- Heidi Ledford
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News & Views |
Chemical beauty contest
Most drug candidates fail clinical trials, in many cases because the compounds have less than optimal physico-chemical properties. A new method for assessing the 'drug-likeness' of compounds might help to remedy the situation.
- Paul Leeson
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Letter |
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist
The X-ray crystal structure of the M2 muscarinic acetylcholine receptor, which is essential for the physiological control of cardiovascular function, is reported.
- Kazuko Haga
- , Andrew C. Kruse
- & Takuya Kobayashi
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News |
Malaria hopes rise as chemists produce cheap artemisinin
Alternate chemical process converts waste product into usable drug.
- Rachel Mundy
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News & Views |
Drugs to awaken a paternal gene
Mutations in the maternal copy of the UBE3A gene cause a neurodevelopmental disorder known as Angelman syndrome. Drugs that activate the normally silenced paternal copy of this gene may be of therapeutic value. See Letter p.185
- Arthur L. Beaudet
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Outlook |
Modernization: One step at a time
The repertoire of traditional Chinese medicine could offer rich pickings for modern drug developers, but researchers must first define and test herbal concoctions.
- Zhiguo Xu
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Letter |
T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction
CBF-β is shown to regulate the ability of HIV-1 to evade host restriction mediated by the deaminase APOBEC3.
- Wenyan Zhang
- , Juan Du
- & Xiao-Fang Yu
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Letter |
Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
Cancer drugs that can potentially treat Angelman syndrome are identified.
- Hsien-Sung Huang
- , John A. Allen
- & Benjamin D. Philpot
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Letter |
Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis
A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts.
- David A. Nagib
- & David W. C. MacMillan
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News |
Blockbuster drug bows out
Pharmaceutical industry anxiously struggles to retool as Lipitor patent expires.
- Heidi Ledford
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Research Highlights |
Gene signature links to drug target
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Outlook |
Translational research: The American way
The United States publishes more biomedical research papers than ever before, yet drug development is stagnating. Several new initiatives aim to turn this knowledge into new remedies.
- Amy Maxmen
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News |
Impossible crystals snag chemistry Nobel
Daniel Shechtman takes award for doggedly pursuing quasicrystals.
- Richard Van Noorden
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Letter |
Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
- Jang Hyun Choi
- , Alexander S. Banks
- & Patrick R. Griffin
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News |
Chemical shortage hampers 'legal high' work
Identification of suspect substances depends on reference materials that are in short supply.
- Daniel Cressey
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Article |
Human metabolic individuality in biomedical and pharmaceutical research
- Karsten Suhre
- , So-Youn Shin
- & Christian Gieger
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News |
Alzheimer's disease genes aid the search for preventive drugs
Proposed trials of candidate drugs before symptoms appear offer hope of more effective treatments.
- David Cyranoski
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Outlook |
Perspective: In search of biomarkers
New methods to follow changes in the brain or blood associated with Alzheimer's disease are critical for developing and testing drugs, says Neil S. Buckholtz.
- Neil S. Buckholtz
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Outlook |
Biomarkers: Warning signs
The hunt is on for biomarkers that signal the descent into Alzheimer's disease. One initiative is leading the pack.
- Ruth Williams
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Outlook |
Drugs: A tangled web of targets
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
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Article |
Structure of the human histamine H1 receptor complex with doxepin
- Tatsuro Shimamura
- , Mitsunori Shiroishi
- & So Iwata
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World View |
Poison in party pills is too much to swallow
The harm caused by designer drugs justifies the law's attempts to keep pace with underground chemists, says Mike Cole.
- Mike Cole
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Letter |
Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation
- Stuart A. Sievers
- , John Karanicolas
- & David Eisenberg
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News & Views |
New lead for pain treatment
The synthesis of conolidine, a scarce, naturally occurring compound, has enabled the first studies of its pharmacological properties to be carried out. Excitingly, conolidine is a painkiller that seems to have an unusual mechanism of action.
- Sarah E. Reisman
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Comment |
Fix the antibiotics pipeline
As resistance mushrooms, governments must make development of new antibiotics financially viable for industry, say Matthew A. Cooper and David Shlaes.
- Matthew A. Cooper
- & David Shlaes
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News |
First lupus drug in half a century approved
A therapeutic antibody is the first success in a wave of experimental therapies aimed at tackling the autoimmune disease.
- Heidi Ledford
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Editorial |
Embrace change
US biomedical scientists should support bold plans to transform the process of drug development. Now is not the time for disunity.
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News Q&A |
Deep future of drug discovery
For GlaxoSmithKline's research chief Patrick Vallance, drug development unites in-house depth with external breadth.
- Daniel Cressey
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Letter |
Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia
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
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News & Views Forum |
A question of library design
Two approaches have emerged for creating libraries of compounds for use in biological screening assays for drug discovery — fragment-based ligand design and diversity-oriented synthesis. Advocates of each approach discuss their favoured strategy.
- Philip J. Hajduk
- , Warren R. J. D. Galloway
- & David R. Spring
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Review Article |
The challenge of new drug discovery for tuberculosis
- Anil Koul
- , Eric Arnoult
- & Koen Andries
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Letter |
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
The mechanism of action of general anaesthetics is poorly understood, although there is some evidence that their principal protein targets are pentameric ligand-gated ion channels (pLGICs). Here, the X-ray crystal structures of propofol and desflurane bound to a bacterial homologue of the pLGIC family are solved. The structures reveal a common binding site for these two anaesthetics in the upper part of the transmembrane domain of each protomer.
- Hugues Nury
- , Catherine Van Renterghem
- & Pierre-Jean Corringer
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News |
Near-action shots of vital proteins
Structures of G-protein-coupled receptors visualized in near-active states.
- Amy Maxmen
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Letter |
The structural basis for agonist and partial agonist action on a β1-adrenergic receptor
Here, the X-ray crystal structure of the β1 adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.
- Tony Warne
- , Rouslan Moukhametzianov
- & Christopher G. Tate
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Article |
Structure of a nanobody-stabilized active state of the β2 adrenoceptor
The X-ray crystal structure of the human β2 adrenergic receptor, a G-protein-coupled receptor, in an agonist-bound 'active' state is solved. Comparison of this structure with a previously published structure of the same GPCR in an inactive state indicates that minor changes in the binding pocket of the protein lead to major changes elsewhere — there is a large outward movement of the cytoplasmic end of one of the transmembrane segments and rearrangements of two other transmembrane segments. This structure provides insights into the process of agonist binding and activation.
- Søren G. F. Rasmussen
- , Hee-Jung Choi
- & Brian K. Kobilka
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World View |
Legal highs: the dark side of medicinal chemistry
Synthetic chemist David Nichols describes how his research on psychedelic compounds has been abused — with fatal consequences.
- David Nichols
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Research Highlights |
Organic chemistry: Making maoecrystal V
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Research Highlights |
Medicine: Profiling for blood pressure