Featured
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High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening
Current tools to test drug metabolism and toxicity in the liver are mainly based on time-consuming traditional cell culture methods. Here Kwon et al.report a high-throughput system employing cells cultured on micropillars that can be transfected with combinations of drug-metabolizing enzymes.
- Seok Joon Kwon
- , Dong Woo Lee
- & Moo-Yeal Lee
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Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease
Beta amyloid aggregation, a process implicated in Alzheimer’s disease pathology, is inhibted by polyoxometalate with a Wells–Dawson structure. Gao et al.show that transition metal-functionalized derivatives are more effective at inhibiting beta amyloid aggregation than non-functionalized derivatives.
- Nan Gao
- , Hanjun Sun
- & Xiaogang Qu
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Activation pathway of Src kinase reveals intermediate states as targets for drug design
Activation of c-src kinase is associated with uncontrolled growth and metastasis of tumour cells. Shukla et al.model conformational changes in c-src during activation, and identify an allosteric site in an intermediate state that may provide a target for small molecule therapeutics.
- Diwakar Shukla
- , Yilin Meng
- & Vijay S. Pande
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| Open AccessDelayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism
The delayed onset of bactericidal activity of the anti-tuberculosis antibiotic bedaquiline is puzzling. Here, Koul and colleagues show, using a multi-omics approach, that the drug triggers a metabolic remodelling in Mycobacterium tuberculosisthat enables the pathogen’s transient survival.
- Anil Koul
- , Luc Vranckx
- & Dirk Bald
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Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Peptide drugs are attractive as therapeutics for gut-based applications, although they may be susceptible to reduction and degradation. Here, the authors develop seleno-oxytocin analogues, with enhanced stability at no cost to potency, and demonstrate their efficacy at colonic nociceptor inhibition in a mouse model.
- Aline Dantas de Araujo
- , Mehdi Mobli
- & Paul F. Alewood
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Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations
PDZ domains facilitate numerous protein-binding interactions, and their prevalence in the human genome has led to their investigation as drug targets. Here, the authors generate semisynthetic PDZ domains containing backbone mutations for the identification of important ligand-binding interactions.
- Søren W. Pedersen
- , Stine B. Pedersen
- & Kristian Strømgaard
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| Open Access4′-O-substitutions determine selectivity of aminoglycoside antibiotics
Aminoglycoside antibiotics target the ribosome but their limited selectivity for the bacterial ribosome can cause side effects in humans. Here, the authors synthesize 4′-O-ether or 4′,6′-O-acetal modifications and show that these compounds possess increased selectivity against bacterial ribosomes.
- Déborah Perez-Fernandez
- , Dmitri Shcherbakov
- & Erik C. Böttger
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Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations
Two antibodies targeting the CεmX domain of membrane-bound IgE on human B lymphocytes are being developed to treat allergy. Here, the authors map the antigenic epitopes of the two antibodies and show that they bind to different conformations of the same peptide region.
- Hsing-Mao Chu
- , Jon Wright
- & Carmay Lim
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Diversity-oriented synthesis as a tool for identifying new modulators of mitosis
Diversity-oriented synthesis is a useful tool to synthesize libraries of structurally complex molecules. Here, the authors show the utility of this method by ultimately identifying a compound causing mitotic arrest and cancer cell death.
- Brett M. Ibbeson
- , Luca Laraia
- & David R. Spring
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Model-based identification of drug targets that revert disrupted metabolism and its application to ageing
Systems biology is considered a promising tool for the identification of new drug targets. Here Yizhak and colleagues present an algorithm to analyse gene expression data and identify potential drug targets that would shift cellular metabolism from a given disease state to that of a healthier state.
- Keren Yizhak
- , Orshay Gabay
- & Eytan Ruppin
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Bio-inspired voltage-dependent calcium channel blockers
Calcium channel blockers are used as treatments for hypertension, angina and pain. Yang et al.show that diverse cytosolic calcium channel-binding proteins act as blockers when targeted to the plasma membrane, and suggest how this property might be used to screen for small-molecule inhibitors.
- Tingting Yang
- , Lin-Ling He
- & Henry M. Colecraft
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Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment
Scn1a encodes a voltage-gated sodium channel and mutations in this gene are implicated in epilepsy. Baraban et al. find that the compound clemizole is effective in blocking epilepsy-like seizures zebrafish with an Scn1adevelopmental mutation.
- Scott C. Baraban
- , Matthew T. Dinday
- & Gabriela A. Hortopan
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| Open AccesshESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury
Astroglia are heterogeneous in phenotype and not all astrocytes are equivalent in their ability to repair injured brain. Here, the authors show that two defined subtypes of astroglia generated from hESC-derived Olig2-positive versus Olig2-negative neural progenitors, exhibit distinct properties and neuroprotective effects.
- Peng Jiang
- , Chen Chen
- & Wenbin Deng
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| Open AccessGenome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets
Genetic interactions can reveal insights into cellular functions. Here, Lu et al.show that negative genetic interactions in protein complexes can be predicted by systematically exploring the evolutionary history of genes, which may be useful for the identification of novel targets for anti-cancer drugs.
- Xiaowen Lu
- , Philip R. Kensche
- & Richard A. Notebaart
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| Open AccessChemical and genetic validation of thiamine utilization as an antimalarial drug target
The malaria parasite Plasmodium falciparum utilizes thiamine for the production of essential enzymatic cofactors. Chan et al. show that inhibition of thiamine utilization with oxythiamine inhibits proliferation of P. falciparumand reduces parasite growth in a mouse model of malaria infection.
- Xie Wah Audrey Chan
- , Carsten Wrenger
- & Kevin J. Saliba
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Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1
The peptide hormone relaxin has potential in the treatment of acute heart failure, but it must be intravenously injected and has a short half-life after administration. Now, small-molecule alternatives to relaxin are reported with similar efficacies to the natural hormone in functional assays.
- Jingbo Xiao
- , Zaohua Huang
- & Juan J. Marugan
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| Open AccessHypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor
The lateral hypothalamus is implicated in drug reward and addiction. Chen and colleagues find that in the lateral hypothalamus of mice, the proteoglycan syndecan-3 negatively regulates cocaine-seeking behaviour by modulating the effects of glial cell line-derived neurotrophic factor.
- Jihuan Chen
- , Vez Repunte-Canonigo
- & Pietro Paolo Sanna
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The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism
The nuclear Farnesoid X receptor (FXR) regulates bile acid and cholesterol production. Here Jin et al. identify the clinically approved antiparasitic drug ivermectin as a novel FXR ligand and show that it has antidiabetic effects in mice.
- Lihua Jin
- , Xuhui Feng
- & Yong Li
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| Open AccessDrug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin
Anthracycline-based drugs can kill cancer cells by inhibiting topoisomerase II and promoting DNA double-strand breaks. Pang et al. show that anthracyclines also induce eviction of histones from open chromatin regions and, in doing so, modulate DNA repair and apoptosis in human cancer cells.
- Baoxu Pang
- , Xiaohang Qiao
- & Jacques Neefjes
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An influenza virus-inspired polymer system for the timed release of siRNA
Small interfering RNA is degraded by plasma and can’t cross the cell membrane due to its negative charge. Here, the authors present an influenza inspired polymer carrier, capable of local RNA delivery, which degrades to a non-toxic by-product, and is thus suitable for multiple doses.
- Nghia P Truong
- , Wenyi Gu
- & Michael J Monteiro
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An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells
Patient-specific induced pluripotent stem (iPS) cells hold great potential for regenerative cell therapies. Here Filareto et al. genetically correct iPS cells from mice with muscular dystrophy and use these cells to treat the same animals, providing a proof-of-principle for autologous iPS cell therapy.
- Antonio Filareto
- , Sarah Parker
- & Rita C. R. Perlingeiro
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High-throughput hyperdimensional vertebrate phenotyping
Large-scale screening of animal phenotypes requires automated detection and analysis of complex morphological information. Here, Yanik and colleagues present an imaging system based on optical projection tomography that generates micrometre-resolution 3D images of zebrafish larvae with within tens of seconds per animal.
- Carlos Pardo-Martin
- , Amin Allalou
- & Mehmet Fatih Yanik
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Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors
Selective inhibitors of protein methyltransferases are anticancer drug candidates. Yu et al. report the structural changes that occur when selective inhibitors bind to the protein methyltransferase DOT1L.
- Wenyu Yu
- , Emma J. Chory
- & Matthieu Schapira
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CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease
L-type calcium channels comprising the CaV1.3 subunit have been linked to the generation of mitochondrial oxidant stress in Parkinson’s disease. Kang et al. identify pyrimidine-2,4,6-triones as a potential molecular scaffold, which they modify to develop a potent and highly selective CaV1.3 antagonist.
- Soosung Kang
- , Garry Cooper
- & Richard B. Silverman
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Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems
Cell-penetrating peptides can be used to deliver nucleic acids and proteins to cells, however they lack selectivity. In this study, cell-penetrating peptides are generated that can selectively target tumour cells of different cellular origins and these may be useful in the treatment of cancer.
- Eisaku Kondo
- , Ken Saito
- & Masayuki Matsushita
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| Open AccessThe translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice
Cachexia, or muscle-wasting syndrome, is often observed in patients with cancer or sepsis, and no specific treatment of cachexia is currently available. In this study, Di Marcoet al.show that low doses of pateamine A, an inhibitor of translation initiation, prevent cachexia in a mouse model of the disease.
- Sergio Di Marco
- , Anne Cammas
- & Imed Eddine Gallouzi
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Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC
Metformin is used to treat diabetes and its use has been associated with reduced cancer incidence, but the mechanism is unclear. In this study, metformin is shown to alter microRNA expression including an increase in mir-33a, which decreases the expression of the oncogenec-Myc.
- Giovanni Blandino
- , Mariacristina Valerio
- & Sabrina Strano
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| Open AccessTargeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury
Claudin-5 is a component of tight junctions and has important roles in mediating the permeability of the blood-brain barrier. Campbell and co-workers administer short interfering RNA against claudin-5 in a model of brain injury, finding that it enhances water movement from the brain to the blood and alleviates swelling.
- Matthew Campbell
- , Finnian Hanrahan
- & Peter Humphries
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| Open AccessDistinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons
Sodium channel Nav1.7 is essential for acute human pain but its role in chronic neuropathic pain is unclear. Minett and colleagues show that Nav1.7 expression specifically in sympathetic neurons, rather than sensory neurons, is required for the development of chronic neuropathic pain after injury.
- Michael S. Minett
- , Mohammed A. Nassar
- & John N. Wood
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| Open AccessCombinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells
Phage display screening can unravel protein–protein interactions, but its application has been mainly restricted to the cell surface. Here, a phage-based reagent is introduced that allows the targeting of combinatorial peptides to cell organelles, providing a tool for the discovery of intracellular ligand-receptors.
- Roberto Rangel
- , Liliana Guzman-Rojas
- & Wadih Arap
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| Open AccessCYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt
Lung injury initiates a series of wound-healing responses, which if unregulated, can lead to fibrosis. Liet al. show that the deubquitinase CYLD has a key role in the prevention of fibrosis by inhibiting transforming growth factor β-signalling through the direct deubiquitination of the protein kinase Akt.
- Jae Hyang Lim
- , Hirofumi Jono
- & Jian-Dong Li
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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol
TRPA1 is a key ion channel in pain signalling. This study shows that activation of TRPA1 in the spinal cord by acetaminophen metabolites and a non-electrophilic cannabinoid produces antinociception that is lost in mice lacking TRPA1, providing an explanation for the analgesic activity of acetaminophen.
- David A Andersson
- , Clive Gentry
- & Peter M Zygmunt
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Metabolomic high-content nuclear magnetic resonance-based drug screening of a kinase inhibitor library
Metabolism is altered in many diseases, and monitoring metabolic changes during treatment could facilitate investigations into treatment efficacy and cellular responses. This study reports an NMR-based method to screen the metabolic responses of mammalian cells to drugs.
- Stefano Tiziani
- , Yunyi Kang
- & Giovanni Paternostro
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Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses
Parasites such as malaria elicit an immune response in their host, causing cytokine levels to increase. In this study, a parasite housekeeping gene, tyrosyl-tRNA synthetase, is shown to bind to host macrophages and, once inside the cells, enhance the levels of proinflammatory cytokines.
- Tarun Kumar Bhatt
- , Sameena Khan
- & Amit Sharma
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A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death
Radiomitigating compounds could be used to protect against ionizing radiation. In this study, mitochondria-targeted oleic and stearic acid derivatives are shown to inhibit pro-apoptotic oxidative events, prevent cell death, and protect mice against lethal doses of radiation.
- Jeffrey Atkinson
- , Alexandr A. Kapralov
- & Valerian E. Kagan
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| Open AccessMechanism of 150-cavity formation in influenza neuraminidase
Group-1 influenza A neuramidase proteins have a 150-cavity that can be targeted by drugs, but the 2009 H1N1 virus neuramidase is not thought to have a 150-cavity. Here, biophysical simulations show that the 2009 H1N1 neuramidase exists in solution with an open 150-cavity, which is stabilized by a salt bridge.
- Rommie E. Amaro
- , Robert V. Swift
- & Robin M. Bush
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Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A
The kinase Dyrk1A is essential for brain function and development, and its excessive activity has been implicated in Down syndrome. In this study, a selective inhibitor of Dyrk1A is developed, which may help to elucidate the molecular mechanisms of normal and diseased brain.
- Yasushi Ogawa
- , Yosuke Nonaka
- & Masatoshi Hagiwara
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Review Article |
Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules
Biologically active molecules can be identified through the screening of small-molecule libraries, but compound collections typically consist of large numbers of structurally similar compounds. Gallowayet al. review how diversity-oriented synthesis can efficiently generate structurally diverse compound libraries.
- Warren R.J.D. Galloway
- , Albert Isidro-Llobet
- & David R. Spring