Article
|
Open Access
Featured
-
-
Article
| Open AccessA small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.
- Naomi Tsuburaya
- , Kengo Homma
- & Hidenori Ichijo
-
Article
| Open AccessHarnessing synthetic lethality to predict the response to cancer treatment
Synthetic lethality (SL) offers a new precision oncology approach, which is based on targeting cancer-specific vulnerabilities across the whole genome, going beyond cancer drivers. The authors develop an approach termed ISLE to identify clinically relevant SL interactions and use them for patient stratification and novel target identification.
- Joo Sang Lee
- , Avinash Das
- & Eytan Ruppin
-
Article
| Open AccessImmuno-detection by sequencing enables large-scale high-dimensional phenotyping in cells
Detecting proteins and post-translational modifications is important for drug screens, but the number of proteins measurable simultaneously is limited. Here the authors use antibodies tagged with DNA barcodes and high-throughput sequencing to detect up to 70 (phospho-)proteins in stem cells.
- Jessie A. G. van Buggenum
- , Jan P. Gerlach
- & Klaas W. Mulder
-
Article
| Open AccessDual-functional peptide with defective interfering genes effectively protects mice against avian and seasonal influenza
A limited number of therapeutics is available to treat influenza A virus (IAV) infections. Here, the authors show that defective interfering genes, delivered with a dual-functional peptide that enables intracellular accumulation and prevents endosomal acidification, inhibit IAV replication in vitro and in vivo.
- Hanjun Zhao
- , Kelvin K. W. To
- & Kwok-Yung Yuen
-
Article
| Open AccessQuantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis
Tumour metastasis is dependent on tumour cell motility. Here, the authors investigate genes required for tumour cell motility by establishing a quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos.
- Konstantin Stoletov
- , Lian Willetts
- & John D. Lewis
-
Article
| Open AccessMale germ cells support long-term propagation of Zika virus
Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with decreased expression of the interferon-stimulated gene Ifi44l.
- Christopher L. Robinson
- , Angie C. N. Chong
- & Shuibing Chen
-
Article
| Open AccessFibrotic microtissue array to predict anti-fibrosis drug efficacy
A bottleneck in developing new anti-fibrosis therapies is the absence of suitable in vitro models that recapitulate key features of fibrogenesis. Here the authors develop a tissue-on-a-chip model of lung fibrosis and test the therapeutic efficacy of two recent FDA-approved drugs.
- Mohammadnabi Asmani
- , Sanjana Velumani
- & Ruogang Zhao
-
Article
| Open AccessTargeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with no present cure. Here the authors perform an in vitro screening leading to the identification of a small molecule that alters the conformational dynamics of the TSL2 RNA structure and acts as a modulator of SMN exon 7 splicing.
- Amparo Garcia-Lopez
- , Francesca Tessaro
- & Leonardo Scapozza
-
Article
| Open AccessA novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration
Mutations that lead to misfolding of rhodopsin can cause retinitis pigmentosa. Here, the authors carry out a high throughput screen to identify a small molecule chaperone of rod opsin, and show that it protects mouse models of retinitis pigmentosa from retinal degeneration.
- Yuanyuan Chen
- , Yu Chen
- & Krzysztof Palczewski
-
Article
| Open AccessCalreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease
Inflammatory bowel disease (IBD) is initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Here, the authors show that inhibition of the calreticulin binding to integrin α subunits ameliorates the severity of IBD in animal models.
- Masayoshi Ohkuro
- , Jun-Dal Kim
- & Akiyoshi Fukamizu
-
Article
| Open AccessOptical functionalization of human Class A orphan G-protein-coupled receptors
G-protein coupled receptors (GPCRs) represent the largest receptor family and are prime drug targets, but many orphan GPCRs are poorly characterized. Here authors engineer human orphan GPCRs to be activated by light which allows studying the receptors ligand identity and downstream signaling.
- Maurizio Morri
- , Inmaculada Sanchez-Romero
- & Harald Janovjak
-
Article
| Open AccessA comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.
- Alison Roth
- , Steven P. Maher
- & John H. Adams
-
Article
| Open AccessPlasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum
Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.
- Selina Bopp
- , Pamela Magistrado
- & Sarah K. Volkman
-
Article
| Open AccessSubstrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site
Sialic acid transporters (SiaT) are required for sialic acid uptake in a number of human pathogens and are of interest as targets for antimicrobial drug development. Here the authors present the substrate bound SiaT structure from the uropathogen Proteus mirabilis and provide insights into the mechanism of sialic acid transport.
- Weixiao Y. Wahlgren
- , Elin Dunevall
- & Rosmarie Friemann
-
Article
| Open AccessThe cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation
Mutations in superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Here the authors present the SOD1 crystal structure bound to the small cysteine-reactive molecule ebselen and show that ebselen is a chaperone for SOD1.
- Michael J. Capper
- , Gareth S. A. Wright
- & S. Samar Hasnain
-
Article
| Open AccessStructural basis for GPR40 allosteric agonism and incretin stimulation
GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism.
- Joseph D. Ho
- , Betty Chau
- & Chafiq Hamdouchi
-
Article
| Open AccessTargeting GLP-1 receptor trafficking to improve agonist efficacy
Glucagon-like peptide-1 receptor (GLP-1R) promotes insulin secretion from pancreatic beta cells and undergoes agonist-mediated endocytosis. Here, authors study GLP-1R endocytosis caused by different agonists and show that a longer plasma membrane retention time of GLP-1R results in greater long-term insulin release.
- Ben Jones
- , Teresa Buenaventura
- & Stephen R. Bloom
-
Article
| Open AccessAggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target
Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.
- Olli Dufva
- , Matti Kankainen
- & Satu Mustjoki
-
Article
| Open AccessHATRIC-based identification of receptors for orphan ligands
Technologies for identifying receptor-ligand pairs on living cells at physiological conditions remain scarce. Here, the authors develop a mass spectrometry-based ligand receptor capture technology that can identify receptors for a diverse range of ligands at physiological pH with as few as a million cells.
- Nadine Sobotzki
- , Michael A. Schafroth
- & Bernd Wollscheid
-
Article
| Open AccessHSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis
Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease
- Margaux Sevin
- , Lucia Kubovcakova
- & Aurélie de Thonel
-
Article
| Open AccessAKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus
Patients suffering from congenital nephrogenic diabetes insipidus (NDI) fail to concentrate urine due to mutations in vasopressin type 2 receptor (V2R). Here Ando et al. show that agents disrupting the interaction between PKA and AKAPs restore aquaporin-2 activity downstream of V2R, offering a therapeutic approach for the treatment of NDI.
- Fumiaki Ando
- , Shuichi Mori
- & Shinichi Uchida
-
Article
| Open AccessSmall tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Anti-TNF therapy has improved the treatment of inflammatory disease but can predispose to infection and malignancy. Here the authors show an anti-TNF biologic peptide that functionally and selectively targets the TNF-p38 pathway in multiple models of inflammation.
- Violet R. Mukaro
- , Alex Quach
- & Antonio Ferrante
-
Article
| Open AccessA DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
Activation of the tumor suppressor p53 is a promising approach in cancer therapy. Here, the authors discover a series of small molecule dihydroorotate dehydrogenase (DHODH) inhibitors that increase p53 synthesis and reduce tumor growth in synergy with the common mdm2 inhibitor nutlin3.
- Marcus J. G. W. Ladds
- , Ingeborg M. M. van Leeuwen
- & Sonia Laín
-
Article
| Open AccessIntegrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer
Triple negative breast cancers harbor multiple copy number aberrations driving gene expression changes thought to underpin their malignant phenotypes. Here the authors integrate these features, finding and functionally validating 37 gene addictions among which they identify the mechanism of addiction to KIFC1, a potential selective drug target.
- Nirmesh Patel
- , Daniel Weekes
- & Andrew N. J. Tutt
-
Article
| Open AccessRapid measurement of inhibitor binding kinetics by isothermal titration calorimetry
There is growing evidence that the kinetics of interactions between inhibitors and their targets can strongly impact therapeutic efficacy. Here the authors describe an isothermal titration calorimetry-based method that can rapidly quantify inhibition kinetics and measure sub-nM binding affinities.
- Justin M. Di Trani
- , Stephane De Cesco
- & Anthony K. Mittermaier
-
Article
| Open AccessCorrelating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria
It is thought that the chances for discovery of novel natural products increase by screening rare organisms. Here the authors analyse metabolites produced by over 2300 myxobacterial strains and, indeed, find a correlation between taxonomic distance and production of distinct secondary metabolite families.
- Thomas Hoffmann
- , Daniel Krug
- & Rolf Müller
-
Article
| Open AccessSelection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity
A subset of chemically-modified siRNAs conjugated to trivalent GalNAc may fail during nonclinical development due to rat hepatotoxicity. Here, the authors show that hepatotoxicity may be accounted for by microRNA-like off-target effects of siRNA and can be mitigated by a thermally destabilizing modification in the siRNA seed region.
- Maja M. Janas
- , Mark K. Schlegel
- & Vasant Jadhav
-
Article
| Open AccessImpaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor
Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.
- David L. Gray
- , John A. Allen
- & Michael D. Ehlers
-
Article
| Open AccessA human endothelial cell-based recycling assay for screening of FcRn targeted molecules
The development of IgG and albumin-based therapeutics with increased half-lives needs more efficient screening procedures. Here the authors report a human endothelial cell-based recycling assay enabling screening of IgG and albumin variants without chemical labelling and prior to animal testing.
- Algirdas Grevys
- , Jeannette Nilsen
- & Jan Terje Andersen
-
Article
| Open AccessA printable hydrogel microarray for drug screening avoids false positives associated with promiscuous aggregating inhibitors
False positive results significantly slow down the drug discovery process. Here, the authors developed a gel serving as a screening platform in which enzymes can be stored, stabilized, and protected from most of the compounds that typically cause these misleading results.
- Rabia Mateen
- , M. Monsur Ali
- & Todd Hoare
-
Correspondence
| Open AccessCorrespondence: Reply to ‘Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury’
- Cheng Xue Qin
- , Lauren T. May
- & Rebecca H. Ritchie
-
Correspondence
| Open AccessCorrespondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury
- Agostino Cilibrizzi
-
Article
| Open AccessA small molecule inhibitor of Rheb selectively targets mTORC1 signaling
Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.
- Sarah J. Mahoney
- , Sridhar Narayan
- & Eddine Saiah
-
Article
| Open AccessCreation of a long-acting nanoformulated dolutegravir
Current ART for treatment of HIV-1 infection requires a strict daily regimen adherence. Herein, the authors report the manufacture and characterization of a nanoformulated dolutegravir prodrug with improved cell and tissue penetration, a remarkable apparent half-life and the potential for bimonthly drug administration.
- Brady Sillman
- , Aditya N. Bade
- & Howard E. Gendelman
-
Article
| Open AccessTarget identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes
Cancer therapy drugs are designed to target genetic vulnerabilities, but loss-of-function screens often fail to identify essential genes in drug mechanism studies. Here the authors demonstrate CRISPRres, which exploits in-frame variation generated by indel formation to discover gene-drug interactions.
- Jasper Edgar Neggers
- , Bert Kwanten
- & Dirk Daelemans
-
Article
| Open AccessRegulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis
Chitinase-3-like-1 (Chi3l1) has been involved in inflammation and pulmonary metastasis. Here the authors show that Chi3l1 inhibits the T cell response by negatively regulating their activation and that, in a mouse model of melanoma, T cell-targeted silencing of Chi3l1 results in reduced lung metastasis.
- Do-Hyun Kim
- , Hong-Jai Park
- & Je-Min Choi
-
Article
| Open AccessActivin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
- John B. Lees-Shepard
- , Masakazu Yamamoto
- & David J. Goldhamer
-
Article
| Open AccessOvercoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics
The plasmid-borne mcr-1 gene confers resistance to the antibiotic colistin. Here, MacNair et al. show that mcr-1 positive bacteria are however susceptible to colistin-mediated disruption of the outer membrane, and can be killed in vitro and in vivo by combining colistin with other antibiotics.
- Craig R. MacNair
- , Jonathan M. Stokes
- & Eric D. Brown
-
Article
| Open AccessBismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors
Metallo-β-lactamases (MBL) are zinc containing enzymes that cause resistance to β-lactam antibiotics. Here the authors show that the anti-Helicobacter pylori drug colloidal bismuth subcitrate inhibits MBLs by displacing the zinc ions with Bi(III), which is of great interest for the development of antibiotics.
- Runming Wang
- , Tsz-Pui Lai
- & Hongzhe Sun
-
Article
| Open AccessStructure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform.
- Anuj Khandelwal
- , Caitlin N. Kent
- & Brian S. J. Blagg
-
Article
| Open AccessCombined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials
Multidrug resistance necessitates novel approaches to treating bacterial infections. Here, the authors apply their high-throughput screening and in silico prediction approaches to show that host receptor tyrosine kinases are good targets for host-directed therapies against intracellular bacteria.
- Cornelis J. Korbee
- , Matthias T. Heemskerk
- & Tom H. M. Ottenhoff
-
Article
| Open AccessFasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling
Stimulant drugs are most commonly used to treat ADHD. Here, the authors demonstrate that in adolescents with ADHD who also have genetic variation in genes impacting metabotropic glutamate signaling, the non-stimulant mGluR activator fasoracetam is well tolerated and may be beneficial in alleviating symptoms of this disease.
- Josephine Elia
- , Grace Ungal
- & Hakon Hakonarson
-
Article
| Open AccessBrain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects
One challenge in drug screening for neurological disorders is how to accurately capture disease pathology and side effects. Here, the authors developed a multi-channel recording platform based on a zebrafish genetic model of epilepsy to screen for antiepileptic drugs.
- Peter M. Eimon
- , Mostafa Ghannad-Rezaie
- & Mehmet Fatih Yanik
-
Article
| Open AccessTarget engagement imaging of PARP inhibitors in small-cell lung cancer
Treatment of small-cell lung cancer remains a challenge due to multiple mechanisms of resistance to current therapies; measuring patient response is crucial in adapting and choosing adequate treatment. Here the authors develop a strategy to visualise in vivo dynamics of a class of widely used PARP inhibitors.
- Brandon Carney
- , Susanne Kossatz
- & Thomas Reiner
-
Article
| Open AccessNF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus
Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.
- Hans D. Brightbill
- , Eric Suto
- & Nico Ghilardi
-
Article
| Open AccessProtein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria
The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.
- Mark A. T. Blaskovich
- , Karl A. Hansford
- & Matthew A. Cooper
-
Article
| Open AccessSmall-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.
- Chensu Wang
- , Hanspeter Niederstrasser
- & Michael A. White
-
Article
| Open AccessMammalian display screening of diverse cystine-dense peptides for difficult to drug targets
Pathologies related to protein:protein interaction are hard to treat but cystine-dense peptides have the potential to disrupt such interactions. Here the authors develop a high-diversity mammalian cell screen for cystine-dense peptides with drug potential and use it to identify a YAP:TEAD inhibitor.
- Zachary R. Crook
- , Gregory P. Sevilla
- & James M. Olson
-
Article
| Open AccessHydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway
Hydralazine is an FDA approved drug for the treatment of hypertension. Here, Dehghan et al. report that hydralazine triggers the cellular oxidative stress response by activating NRF2/SKN-1 signaling and extends C. elegans healthy lifespan, suggesting hydralazine may have potential to treat age-associated diseases more broadly.
- Esmaeil Dehghan
- , Yiqiang Zhang
- & Hamid Mirzaei