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| Open AccessInhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
Delta-secretases are associated with Alzheimer’s disease (AD) as they cleave both amyloid precursor protein and tau. Here the authors develop a series of orally bioactive small molecule delta-secretase inhibitors and report its therapeutic effects in mouse models of AD.
- Zhentao Zhang
- , Obiamaka Obianyo
- & Keqiang Ye
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Article
| Open AccessThe structure of Zika virus NS5 reveals a conserved domain conformation
The recent outbreak of Zika virus is a major worldwide health concern and effective drugs are currently not available. Here the authors present the structure of Zika non-structural protein 5 and identify a potential drug-binding site, which might facilitate the development of novel antivirals.
- Boxiao Wang
- , Xiao-Feng Tan
- & Jikui Song
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| Open AccessCrystal structure of Zika virus NS5 RNA-dependent RNA polymerase
The Zika virus outbreak is a global health threat and there is an urgent need for drugs against the virus. Here the authors present the structure of the RNA-dependent RNA-polymerase domain from Zika non-structural protein 5, which is a template for the design of non-nucleoside polymerase inhibitors.
- Andre S. Godoy
- , Gustavo M. A. Lima
- & Glaucius Oliva
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Article
| Open AccessA chemical chaperone improves muscle function in mice with a RyR1 mutation
Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.
- Chang Seok Lee
- , Amy D. Hanna
- & Susan L. Hamilton
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Article
| Open AccessLong-acting protein drugs for the treatment of ocular diseases
Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.
- Joy G. Ghosh
- , Andrew A. Nguyen
- & Michael Roguska
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| Open AccessPharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice
The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.
- Martina Schweiger
- , Matthias Romauch
- & Rudolf Zechner
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Article
| Open AccessA potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibitsPlasmodium falciparum in vitroand in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.
- Ebere Sonoiki
- , Caroline L. Ng
- & Philip J. Rosenthal
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| Open AccessAdministration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge
Monoclonal antibodies are highly effective therapeutics that can be delivered as proteins or encoded DNA or mRNA. Here the authors develop lipid nanoparticle-formulated nucleoside-modified mRNA encoding an HIV-1 neutralizing antibody and see sustained and protective antibody levels in treated mice.
- Norbert Pardi
- , Anthony J. Secreto
- & Drew Weissman
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Article
| Open AccessFluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice
Bisphenol A is used in the production of many plastic products, but has adverse health effects and is therefore being replaced. Here the authors show that its substitute, fluorene-9-bisphenol, is released from commercial plastic bottles into drinking water, and has anti-oestrogenic effects in mice.
- Zhaobin Zhang
- , Ying Hu
- & Jianying Hu
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Article
| Open AccessIn situ click chemistry generation of cyclooxygenase-2 inhibitors
Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.
- Atul Bhardwaj
- , Jatinder Kaur
- & Frank Wuest
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Article
| Open AccessArylmethylamino steroids as antiparasitic agents
Steroid units can facilitate membrane permeation and bioavailability in drugs. Here, using a medicinal chemistry program, Krieget al. identify an arylmethylamino steroid that kills Plasmodium parasites, likely through a chelate-based quinone methide mechanism, and has activity against Schistosoma mansoni.
- Reimar Krieg
- , Esther Jortzik
- & Katja Becker
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Article
| Open AccessTumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma
Head and neck squamous cell carcinomas (HNSCC) often harbourPIK3CAmutations but PI3Kα inhibitors can cause some side effects. Here, the authors develop P-selectin targeted nanoparticles to enhance tumour-specific delivery of a PI3Kα inhibitor to HNSCC PDX and orthotopic xenograft models.
- Aviram Mizrachi
- , Yosi Shamay
- & Maurizio Scaltriti
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Article
| Open AccessMolecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.
- Moritz Schütte
- , Thomas Risch
- & Marie-Laure Yaspo
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Article
| Open AccessReconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions
The rat is a widely-used model for human biology, but we must be aware of metabolic differences. Here, the authors reconstruct the genome-scale metabolic network of the rat, and after reconciling it with an improved human metabolic model, demonstrate the power of the models to integrate toxicogenomics data, providing species-specific biomarker predictions in response to a panel of drugs.
- Edik M. Blais
- , Kristopher D. Rawls
- & Jason A. Papin
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Article
| Open AccessSmall-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice
G Protein-Coupled Receptors (GPCRs) can adopt different conformations, each linked to distinct cellular outcomes. Here the authors show that compound 17b, a novel agonist of the GPCR family member FPR, robustly activates cardioprotective but not detrimental FPR signalling, showing beneficial therapeutic effect in a mouse model of cardiac infarction.
- Cheng Xue Qin
- , Lauren T. May
- & Rebecca H. Ritchie
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Article
| Open AccessDissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo
Goadsporin is an antibacterial peptide highly customized by multiple post-translational modifying enzymes. Here, the authors dissect its biosynthetic pathway byin vitro reconstitution and use their insights to produce goadsporin analogues in vitro and in vivo.
- Taro Ozaki
- , Kona Yamashita
- & Hiroyasu Onaka
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Article
| Open AccessSC83288 is a clinical development candidate for the treatment of severe malaria
Severe malaria is a life-threatening infection with limited treatment options. Here, using a medicinal chemistry approach starting from amicarbalide, Pegoraroet al. identify a compound that, when delivered intravenously, can cure Plasmodium falciparuminfection in a humanized mouse model.
- Stefano Pegoraro
- , Maëlle Duffey
- & Michael Lanzer
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Article
| Open AccessDrug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time
Current antibiotic therapies for tuberculosis are lengthy and onerous. Here, the authors use an output-driven approach to optimize drug doses for two experimental drug regimens in a mouse model of tuberculosis, leading to improved regimens that reduce treatment time by 75%.
- Bai-Yu Lee
- , Daniel L. Clemens
- & Marcus A. Horwitz
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| Open AccessEsterase mutation is a mechanism of resistance to antimalarial compounds
Pepstatin is a known inhibitor of malarial proteases, but its activity varies between sources. Here, Istvanet al. identify a pepstatin ester as the active component of pepstatin preparations and show that this prodrug is activated by a Plasmodiumesterase, mutation of which can confer resistance to pepstatin and other compounds.
- Eva S. Istvan
- , Jeremy P. Mallari
- & Daniel E. Goldberg
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| Open AccessA broadly protective therapeutic antibody against influenza B virus with two mechanisms of action
Influenza B virus (IBV) co-circulates with influenza A virus to cause annual epidemics. Here, Chaiet al. isolate a human monoclonal antibody that binds to a conserved epitope in the viral HA protein, neutralizes IBV strains in vitro, and protects mice against IBV infection.
- Ning Chai
- , Lee R. Swem
- & Man-Wah Tan
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| Open AccessCannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
CB2 receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB2 receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivostudies.
- Marjolein Soethoudt
- , Uwe Grether
- & Mario van der Stelt
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| Open AccessFunctional screening for anti-CMV biologics identifies a broadly neutralizing epitope of an essential envelope protein
Human cytomegalovirus (CMV) poses a risk for immunosuppressed patients and newborns, with limited treatment options available. Here, Gardneret al. use a high-throughput approach and identify monoclonal antibodies that bind a highly conserved domain in the viral glycoprotein gH as potent inhibitors of CMV infection.
- Thomas J. Gardner
- , Kathryn R. Stein
- & Domenico Tortorella
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| Open AccessAilanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer
Prostate cancers often become castration resistant due to alternative expression of androgen receptor (AR) splice variants. Here, the authors screened a library of natural compounds and identified Ailanthone as a potent inhibitor of AR through its binding to the co-chaperone protein p23 that, by preventing AR interaction with HSP90, results in ubiquitin/proteasome-mediated degradation of the receptor.
- Yundong He
- , Shihong Peng
- & Mingyao Liu
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Article
| Open AccessMEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated
ATM is a tumor suppressor often mutated in lung adenocarcinoma. In this study, the authors starting from a synthetic lethal screen, demonstrate that tumor cells with mutations in ATM exhibit increased sensitivity to MEK1/2 inhibition through the modulation of the AKT/mTOR pathway.
- Michal Smida
- , Ferran Fece de la Cruz
- & Sebastian M. B. Nijman
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Article
| Open AccessTotal synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation
Feglymycin is a biologically active peptide but a challenging synthetic target due to the highly racemizable nature of the 3,5-dihydroxyphenylglycine groups. Here the authors report the synthesis of feglymycin using a microflow system, allowing amide bond formation without severe racemization.
- Shinichiro Fuse
- , Yuto Mifune
- & Hiroshi Tanaka
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| Open AccessLiver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis
Statins are lipid-lowering drugs that prevent cardiovascular disease but tolerability is limited by severe side effects in muscles. Here the authors elucidate a liver-specific activation mechanism for bempedoic acid, a novel cholesterol-lowering drug, and show how it effectively reduces LDL-C and atherosclerotic burden in mice, but does not cause myotoxicty.
- Stephen L. Pinkosky
- , Roger S. Newton
- & Narendra D. Lalwani
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Article
| Open AccessTheranostic barcoded nanoparticles for personalized cancer medicine
Determining the most effective treatment for each cancer patient is a key challenge in cancer therapy. In this article, the authors show, in a mouse model of breast cancer, that DNA barcoded nanoparticles can be used for pre-screening the efficacy of anticancer drugs.
- Zvi Yaari
- , Dana da Silva
- & Avi Schroeder
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| Open AccessThe antifungal caspofungin increases fluoroquinolone activity against Staphylococcus aureus biofilms by inhibiting N-acetylglucosamine transferase
Biofilms formed byStaphylococcus aureus are poorly responsive to antibiotics. Here, Siala et al. show that an antifungal drug (caspofungin) enhances the activity of fluoroquinolone antibiotics against S. aureus biofilms by inhibiting an enzyme involved in synthesis of the biofilm matrix.
- Wafi Siala
- , Soňa Kucharíková
- & Françoise Van Bambeke
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| Open AccessTargeted inhibition of the COP9 signalosome for treatment of cancer
Dysregulation of protein degradation by the ubiquitin-proteasome system is a feature commonly associated with cancer. Here, the authors develop an orally available small molecule that inhibits CSN5, the proteolytic subunit of the COP9 signalosome, and blocks tumour growth in a xenograft model.
- Anita Schlierf
- , Eva Altmann
- & Bruno Martoglio
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| Open AccessStructures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes
Leishmania donovani is a protozoan parasite that can cause fatal infections in humans. Here the authors present a high resolution cryoEM structure of the L. donovani80S ribosome and compare it to its human counterpart to provide insight into the basis for drug selectivity towards this eukaryotic parasite.
- Xing Zhang
- , Mason Lai
- & Z. Hong Zhou
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| Open AccessChemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.
- Andrea M. Zuhl
- , Charles E. Nolan
- & Douglas S. Johnson
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| Open AccessLarge-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model
Large-scale screens on whole animals could facilitate drug discovery, but are technically challenging. Here, Mondal et al. develop a microfluidic chip combined with an automated imaging platform that enables high-throughput, high-resolution screening of Caenorhabditis elegansdisease models.
- Sudip Mondal
- , Evan Hegarty
- & Adela Ben-Yakar
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| Open AccessMechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor
Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform overexpressed in several cancers that has been implicated in drug resistance. Here the authors identify a small molecule inhibitor of GSTO1 that effectively inhibits tumor growth in colon cancer models, and establish its mechanism of action.
- Kavya Ramkumar
- , Soma Samanta
- & Nouri Neamati
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| Open AccessAnti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
Drugs that sensitize tumour cells to ionizing radiation are prized because they can overcome resistance to radiotherapy. Here, the authors show that anti-tubulin drugs conjugated to cetuximab or trastuzumab can radiosensitize EGFR- or HER2-expressing tumors by increasing DNA damage and cell death due to ionizing radiation.
- Stephen R. Adams
- , Howard C. Yang
- & Sunil J. Advani
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| Open AccessIrreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments
Molecular fragments are useful tools in drug-discovery but they might be hard to identify due to their weak affinity to the targets. Here, the authors use a protein-templated assembly to design high affinity inhibitors of Coxsackie virus 3C protease, a pharmacological target against enteroviral infections.
- Daniel Becker
- , Zuzanna Kaczmarska
- & Jörg Rademann
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| Open AccessExtraction and analysis of signatures from the Gene Expression Omnibus by the crowd
A wealth of gene expression data is publicly available, yet is little use without additional human curation. Ma’ayan and colleagues report a crowdsourcing project involving over 70 participants to annotate and analyse thousands of human disease-related gene expression datasets.
- Zichen Wang
- , Caroline D. Monteiro
- & Avi Ma’ayan
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| Open AccessFragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities
Cyclophilins play a key role in the life cycle of many viruses and represent important drug targets for broad-spectrum antiviral therapies. Here, the authors use fragment-based drug discovery to develop non-peptidic inhibitors of human cyclophilins with high activity against replication of a number of viral families.
- Abdelhakim Ahmed-Belkacem
- , Lionel Colliandre
- & Jean- François Guichou
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Article
| Open AccessNeutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
- Linda Labberton
- , Ellinor Kenne
- & Thomas Renné
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Article
| Open AccessIdentification of KasA as the cellular target of an anti-tubercular scaffold
Screens for bactericidal compounds have resulted in promising anti-tubercular hits. Here, the authors analyse in detail the target of an indazole sulfonamide (GSK3011724A), and find that it has a different mode of inhibition compared to other Kas inhibitors of fatty acid biosynthesis in bacteria.
- Katherine A. Abrahams
- , Chun-wa Chung
- & Robert H. Bates
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Article
| Open AccessAtezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma
Cancer immunotherapy can be used in combination with other therapies for a better response. Here, the authors conduct a phase Ib clinical study and report the clinical activity and the immune response of the anti-PDL1 agent, atezolizumab, in combination with bevacizumab in ten patients with metastatic renal cell carcinoma.
- Jeffrey J. Wallin
- , Johanna C. Bendell
- & David F. McDermott
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Article
| Open AccessProbiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis
Probiotics have tumour-suppressive effects in cancer cell lines and in animal models. In this study, the authors demonstrate that ferrichrome produced by Lactobacillus caseiATCC334 can suppress colon cancer growth inducing apoptosis via the JNK pathway.
- Hiroaki Konishi
- , Mikihiro Fujiya
- & Yutaka Kohgo
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Article
| Open AccessCell-permeable succinate prodrugs bypass mitochondrial complex I deficiency
Mitochondrial complex I deficiency is the most common respiratory chain defect in mitochondrial disease in children and currently there is no effective treatment. In this study, the authors show that succinate prodrugs can alleviate metabolic decompensation in Leigh syndrome patient fibroblasts.
- Johannes K. Ehinger
- , Sarah Piel
- & Eskil Elmér
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Article
| Open AccessSynthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care
Current biopharmaceutical manufacturing platforms use single biologic-producing cell lines cultured at large scales. Here the authors develop a small-scale, portable biomanufacturing platform to produce single dose IFNa2b and rHGH from a single engineered strain of P. pastoris.
- Pablo Perez-Pinera
- , Ningren Han
- & Timothy K. Lu
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| Open AccessMultiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis
Human parechovirus 3 (HPeV3) can cause severe central nervous system infections and is a major cause of neonatal sepsis. Here the authors determine the structure of HPeV3 that provides a high-resolution view of the capsid’s organization and shows multiple interactions of the RNA genome with coat proteins.
- Shabih Shakeel
- , Brenda M. Westerhuis
- & Sarah J. Butcher
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Article
| Open AccessTreatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells
Evidence of how functional Bregs develop in vivo has been lacking. Here the authors show that proB cells exposed in vivoto CpG differentiate into distinct Breg subsets that inhibit autoimmunity by arresting T cells in the lymph nodes via CCL19 and by producing IL-10 at the site of immunopathology.
- Sarantis Korniotis
- , Christophe Gras
- & Flora Zavala
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| Open AccessEngineering biosynthesis of the anticancer alkaloid noscapine in yeast
Noscapine is a potential anticancer drug that is traditionally isolated from the opium poppy Papaver somniferum. Here, Li and Smolke reconstitute the noscapine gene cluster in Saccharomyces cerevisiae, to achieve the microbial production of noscapine and related pathway intermediates, and provide new insights into the biosynthesis of noscapine.
- Yanran Li
- & Christina D. Smolke
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Article
| Open AccessTranslation control during prolonged mTORC1 inhibition mediated by 4E-BP3
The eIF4E-binding proteins (4E-BPs) are critical repressors of cap-dependent translation via mTOR, a pathway frequently hyperactivated in cancer. Here the authors show that 4E-BP3 specifically mediates the cap-dependent translation repression and antiproliferative effects of prolonged pharmacological mTOR inhibition.
- Yoshinori Tsukumo
- , Tommy Alain
- & Nahum Sonenberg
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Article
| Open AccessDesign of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10
Expanded RNA repeats in non-coding region of a gene represent a hallmark of several diseases. Here, the authors identify two small molecules that selectively bind AU repeats and use them to design a compound that targets the pathogenic RNA associated with spinocerebellar ataxia type 10.
- Wang-Yong Yang
- , Rui Gao
- & Matthew D. Disney
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Article
| Open AccessA bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair
Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.
- Monica Florio
- , Kannan Gunasekaran
- & Michael S. Ominsky