Target identification articles within Nature Communications

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  • Article
    | Open Access

    Quantitative profiling of small molecule-protein binding in cells can aid basic biochemical research and drug discovery. Here, the authors develop the Heat Shock Protein Inhibition Protein Stability Assay (HIPStA) as a high-throughput method to assess cellular target engagement and identify new drug targets.

    • Kelvin F. Cho
    • , Taylur P. Ma
    •  & Robert A. Blake

  • Article
    | Open Access

    The important tuberculosis drug pyrazinamide (PZA) is converted to its active form pyrazinoic acid (POA) in Mycobacterium tuberculosis (Mtb). Here the authors identify the pantothenate biosynthesis pathway enzyme aspartate decarboxylase (PanD) as the target of PZA and determine the POA bound Mtb PanD crystal structure.

    • Qingan Sun
    • , Xiaojun Li
    •  & James C. Sacchettini

  • Article
    | Open Access

    Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.

    • Fabian Hulpia
    • , Dorien Mabille
    •  & Serge Van Calenbergh

  • Article
    | Open Access

    Drug target identification is a crucial step in drug development. Here, the authors introduce a Bayesian machine learning framework that integrates multiple data types to predict the targets of small molecules, enabling identification of a new set of microtubule inhibitors and the target of the anti-cancer molecule ONC201.

    • Neel S. Madhukar
    • , Prashant K. Khade
    •  & Olivier Elemento

  • Article
    | Open Access

    Amino acid biosynthetic pathways are an attractive alternative to treat chronic infections such as Mycobacterium tuberculosis (Mtb). Here, the authors investigate the metabolic response to disruption of the aspartate pathway in persistent Mtb and identify essential enzymes as potential new targets for drug development.

    • Erik J. Hasenoehrl
    • , Dannah Rae Sajorda
    •  & Michael Berney

  • Article
    | Open Access

    Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.

    • Melusine Bleu
    • , Swann Gaulis
    •  & Giorgio G. Galli

  • Article
    | Open Access

    Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD+ synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD+ levels in cultured cells and elevates liver NAD+ in mice.

    • Stephen J. Gardell
    • , Meghan Hopf
    •  & Anthony B. Pinkerton

  • Article
    | Open Access

    Membrane proteins have been implicated in cancers, but studying the downstream effects of their perturbation remains challenging. Here, the authors map the membrane protein-regulated network of 15 cancers, a resource for prognostic biomarker development and druggable target identification.

    • Chun-Yu Lin
    • , Chia-Hwa Lee
    •  & Jinn-Moon Yang

  • Article
    | Open Access

    The use of nonsteroidal anti-inflammatory drugs inhibiting COX-1/2 is associated with an increased risk of heart failure. Here the authors show that mPGES-1, a therapeutic target downstream of COX enzymes, protects from cardiac ischemia/reperfusion injury, limiting leukocyte-endothelial interactions and preserving microvascular perfusion partly via the endothelial EP4 receptor.

    • Liyuan Zhu
    • , Chuansheng Xu
    •  & Miao Wang

  • Article
    | Open Access

    Combination therapy holds great promise, but discovery remains challenging. Here, the authors propose a method to identify efficacious drug combinations for specific diseases, and find that successful combinations tend to target separate neighbourhoods of the disease module in the human interactome.

    • Feixiong Cheng
    • , István A. Kovács
    •  & Albert-László Barabási

  • Article
    | Open Access

    Heterologous production of the glycocins, posttranslationally modified peptide bacteriocins containing a sugar moiety, has not been achieved. Here, the authors express a thermophilic bacterium glycocin biosynthetic gene cluster and S-glycosyltransferase for the production of antibacterial glycocins in E. coli.

    • Arnoldas Kaunietis
    • , Andrius Buivydas
    •  & Oscar P. Kuipers

  • Article
    | Open Access

    Mother Nature is a valuable resource for the discovery of drug and agricultural chemicals. Here, the authors show that 7-deoxy-sedoheptulose produced by a cyanobacterium is an antimicrobial and herbicidal compound that acts through inhibition of 3-dehydroquniate synthase in the shikimate pathway.

    • Klaus Brilisauer
    • , Johanna Rapp
    •  & Karl Forchhammer

  • Article
    | Open Access

    Genetic screens are important tools to identify host factors associated with viral infections. Here, Flint et al. perform a genome-wide CRISPR screen using infectious Ebola virus (EBOV) and show that the host transferase GNPTAB is required for EBOV infection and a potential target for antiviral therapies

    • Mike Flint
    • , Payel Chatterjee
    •  & Christina F. Spiropoulou

  • Article
    | Open Access

    Viruses rely on host cell metabolism for replication, making these pathways potential therapeutic targets. Here, the authors show that AM580, a retinoid derivative and RAR-α agonist, affects replication of several RNA viruses by interfering with the activity of SREBP.

    • Shuofeng Yuan
    • , Hin Chu
    •  & Kwok-Yung Yuen

  • Article
    | Open Access

    Direct targeting of mutant KRas is challenging and alternative approaches are needed. Here they show glycogen synthase kinase 3 (GSK3) to be required for the growth and survival of human mutant KRas-dependent tumors but dispensable for mutant KRas-independent tumors and show GSK3 inhibition to inhibit in vivo growth of Kras mutant patient-derived pancreatic tumors.

    • Aslamuzzaman Kazi
    • , Shengyan Xiang
    •  & Saïd M. Sebti

  • Article
    | Open Access

    Myotubular myopathy is a severe muscle disease for which no effective treatment exists. Here, the authors show that tamoxifen ameliorates pathology and extends survival in a mouse model of the disease, and that the effect is mediated via estrogen receptor signaling and involves modulation of DNM2 expression.

    • Nika Maani
    • , Nesrin Sabha
    •  & James J. Dowling

  • Article
    | Open Access

    The identification of new drug targets is highly challenging, particularly for diseases of the brain. This study describes a general computational gene regulatory framework called CRAFT for drug target discovery, and the authors use CRAFT to identify the microglial membrane receptor Csf1R as a potential therapeutic target for epilepsy.

    • Prashant K. Srivastava
    • , Jonathan van Eyll
    •  & Michael R. Johnson

  • Article
    | Open Access

    The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.

    • Hongbin He
    • , Hua Jiang
    •  & Rongbin Zhou

  • Article
    | Open Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    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 Access

    E3 ubiquitin ligases regulate biological functions by ubiquitinating defined substrate proteins but overlapping specificities complicate the identification of E3-substrate relationships. Here, the authors construct an orthogonal UB transfer cascade and identify specific substrates of the E3 enzyme E6AP.

    • Yiyang Wang
    • , Xianpeng Liu
    •  & Jun Yin

  • Article
    | Open Access

    Small molecules correcting the splicing deficit of the survival of motor neuron 2 (SMN2) gene have been identified as having therapeutic potential. Here, the authors provide evidence that SMN2 mRNA forms a ribonucleoprotein complex that can be specifically targeted by these small molecules.

    • Manaswini Sivaramakrishnan
    • , Kathleen D. McCarthy
    •  & Friedrich Metzger

  • Article
    | Open Access

    Masitinib is a protein kinase inhibitor that sensitises refractory pancreatic adenocarcinoma cells to treatment with the nucleoside analog gemcitabine. Here the authors show that Masitinib activates deoxycytidine kinase to enhance phosphorylation of nucleoside analogue pro-drugs, increasing their potency.

    • Kahina Hammam
    • , Magali Saez-Ayala
    •  & Patrice Dubreuil

  • Article
    | Open Access

    TREKs are members of the two-pore domain potassium (K2P) channels, being important clinical targets. Here the authors identify inhibitors of K2P that bind to an allosteric site located in their extracellular cap, suggesting that it might be a promising drug target for these channels.

    • Qichao Luo
    • , Liping Chen
    •  & Huaiyu Yang

  • Article
    | Open Access

    Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.

    • Carl A. Machutta
    • , Christopher S. Kollmann
    •  & Ghotas Evindar

  • Article
    | Open Access

    Cells infected with Epstein-Barr virus (EBV) express the virus-encoded EBNA1, which is essential for viral genome maintenance but also highly antigenic. Here the authors implicate nucleolin as a host factor that mediates the repression of EBNA1-derived antigenic peptides through binding of the G4-quadruplex structure present within the EBNA1 mRNA.

    • María José Lista
    • , Rodrigo Prado Martins
    •  & Marc Blondel

  • Article
    | Open Access

    Ethylene is a plant hormone that promotes fruit ripening. Here, the authors identify pyrazinamide, a drug used to treat tuberculosis, as an inhibitor of ethylene biosynthesis inArabidopsis thalianaand present the crystal structure of its active form (pyrazinecarboxylic acid) bound to ACC oxidase.

    • Xiangzhong Sun
    • , Yaxin Li
    •  & Hongwei Guo

  • Article
    | Open Access

    There are no robust methods for systematically identifying mutation-specific synthetic lethal (SL) partners in cancer. Here, the authors develop a computational algorithm that uses pan-cancer data to detect mutation-andcancer-specific SL partners and they validate a novel SL interaction between mutant IDH and loss of ACACA in leukaemia.

    • Subarna Sinha
    • , Daniel Thomas
    •  & David L. Dill

  • Article
    | Open Access

    Steviol glycosides are sweet-tasting compounds isolated from a South American shrub and are increasingly used as sweeteners in foods and beverages. Philippaertet al. demonstrate that steviol glycosides potentiate Ca2+-dependent TRPM5 activity and promote glucose-induced insulin secretion and glucose tolerance.

    • Koenraad Philippaert
    • , Andy Pironet
    •  & Rudi Vennekens

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.

    • Andrew L. Hong
    • , Yuen-Yi Tseng
    •  & Jesse S. Boehm

  • Article
    | Open Access

    FR171456 is a bioactive chemical produced by some microorganisms. Here, the authors identify the enzyme NSDHL of the sterol synthesis pathway as the molecular target of FR171456, rendering it the first compound to specifically target this class of enzyme in yeast and mammalian cells.

    • Stephen B. Helliwell
    • , Shantanu Karkare
    •  & Christian N. Parker

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