Drug discovery articles within Nature Communications

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  • Article
    | Open Access

    Chikungunya virus is a mosquito transmitted untreatable emergent pathogen that causes joint pain and fever. Here the authors perform a host genome-wide loss-of-function screen to identify targets for chikungunya antiviral drugs and validate hits using a mouse model of chikungunya infection.

    • Alexander Karlas
    • , Stefano Berre
    •  & Marc Lecuit

  • Article
    | Open Access

    Intrinsically disordered proteins that form amyloid fibrils are hard to target with traditional therapeutic approaches. Here, the authors report on an oligoquinoline derivative that binds the human islet amyloid polypeptide, stabilising an alpha-helical structure that reduces its cellular toxicity.

    • Sunil Kumar
    • , Melissa Birol
    •  & Andrew D. Miranker

  • Article
    | Open Access

    PDEδ is a widely expressed factor that sustains the spatial organization and signalling of Ras family proteins. Here the authors describe the activity of Deltazinone 1, a new highly selective PDEδ inhibitor of KRAS-dependent cancer cell growth with low cytotoxic side effects.

    • Björn Papke
    • , Sandip Murarka
    •  & Philippe I.H. Bastiaens

  • Article
    | Open Access

    Understanding the basis of odour perception and discrimination is a challenging task, due to the inherent complexity of the olfactory system. Here, the authors use a medicinal chemistry approach to derive biologically relevant rules for odorant classification.

    • Erwan Poivet
    • , Zita Peterlin
    •  & Stuart Firestein

  • Article
    | Open Access

    Drugs therapeutic efficacy relies on their capability of binding the relevant targets in a physiological environment, which has so far been hard to measure. Here, the authors present a compound library screen based on a target engagement assay that reports on protein stability upon ligands binding in cell.

    • Helena Almqvist
    • , Hanna Axelsson
    •  & Pär Nordlund

  • Article
    | Open Access

    Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.

    • Ricardo Sant'Anna
    • , Pablo Gallego
    •  & Salvador Ventura

  • Article
    | Open Access

    Progress in drug discovery can be hampered by a limited exploration of chemical space and the difficulty in assessing the full range of drug candidates’ effects on living cells. Here the authors describe a cell-based assay to distinguish between off-target and specific effects of candidate compounds targeting micro RNAs.

    • Benjamin Haefliger
    • , Laura Prochazka
    •  & Yaakov Benenson

  • Article
    | Open Access

    Charged phosphorylated metabolite such as nucleoside tri-phosphates exhibit poor membrane permeability due to their high polarity, limiting their utility as drugs or cellular probes. Here the authors develop a method to render nucleoside triphosphates cell permeable and allows their release by an enzyme-triggered mechanism.

    • Tristan Gollnest
    • , Thiago Dinis de Oliveira
    •  & Chris Meier

  • Article
    | Open Access

    The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.

    • Jihui Ping
    • , Tiago J.S. Lopes
    •  & Yoshihiro Kawaoka

  • Article
    | Open Access

    Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin in clinical trials for treatment of systolic heart failure. Here the authors determine the crystal structure of an OM-bound human β-cardiac myosin motor domain to provide molecular level insight into the mechanism of drug action.

    • Donald A. Winkelmann
    • , Eva Forgacs
    •  & Ann M. Stock

  • Article
    | Open Access

    The inhibition of bacterial glycosyltransferase has the potential to be an effective therapeutic target against drug resistance bacteria. Here, the authors present a novel class of inhibitor compounds based on a monosaccharide scaffold, which are able to eliminate bacterial infections in mice.

    • Johannes Zuegg
    • , Craig Muldoon
    •  & Matthew A. Cooper

  • Article
    | Open Access

    Tuberculosis control is threatened by the continued emergence of drug-resistant strains. Here, Rybniker et al. screen a library of FDA-approved drugs and identify a gastric proton pump inhibitor that also has antituberculosis activity and targets the bacterial cytochrome bc1complex.

    • Jan Rybniker
    • , Anthony Vocat
    •  & Stewart T. Cole

  • Article
    | Open Access

    Sirtuins are NAD+-dependent deacylases implicated in the regulation of stress responses, bioenergetics and epigenetic control. Here the authors describe the crystal structure of a sirtuin-activating compounds (STAC)-sirtuin complex and begin to elucidate the mechanism of sirtuins activation by STACs.

    • Han Dai
    • , April W. Case
    •  & James L. Ellis

  • Article
    | Open Access

    Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.

    • Andrew R. Burns
    • , Genna M. Luciani
    •  & Peter J. Roy

  • Article
    | Open Access

    Ganoderma lucidumis a medicinal mushroom used in Traditional Chinese Medicine with putative anti-diabetic properties. Here, the authors show that polysaccharides from a water extract of this mushroom exert beneficial metabolic effects by modulating the composition of the gut microbiota in mice.

    • Chih-Jung Chang
    • , Chuan-Sheng Lin
    •  & Hsin-Chih Lai

  • Article
    | Open Access

    Fatty acids are ancient lipids with numerous functions, from metabolic processes as a source of energy to structural and signalling roles within cell membranes. Here, the authors present azobenzene-modified fatty acids and their application as photoswitchable agonists of the Vanilloid Receptor 1.

    • James Allen Frank
    • , Mirko Moroni
    •  & Dirk Trauner

  • Article |

    Cystic fibrosis is a lethal genetic disorder commonly caused by the F508del mutation which is not amenable to gene therapy. Here, the authors use triplex-forming PNA molecules and donor DNA in biodegradable polymer nanoparticles to correct F508del and achieve clinically relevant levels of gene editing.

    • Nicole Ali McNeer
    • , Kavitha Anandalingam
    •  & Marie E. Egan

  • Article |

    The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al, show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.

    • Vinodkumar B. Pillai
    • , Sadhana Samant
    •  & Mahesh P. Gupta

  • Article
    | Open Access

    Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAAas the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.

    • William T. Ralvenius
    • , Dietmar Benke
    •  & Hanns Ulrich Zeilhofer

  • Article |

    Inhibiting the interaction between the membrane protein P-selectin and its ligand PSGL-1 is thought to block inflammation. Here the authors report an efficient stereoselective synthesis for PSGL-1 glycopeptide mimics and show that these compounds inhibit PSGL-1/P-selectin in vitro and in vivo.

    • Venkata R. Krishnamurthy
    • , Mohammed Y. R. Sardar
    •  & Elliot L. Chaikof

  • Article
    | Open Access

    The emergence of resistant Plasmodiumstrains fuels the search for new antimalarials. Here, the authors present a new class of potent antimalarial compounds, the triaminopyrimidines, that display low toxicity and long half-life in animal models.

    • Shahul Hameed P.
    • , Suresh Solapure
    •  & Vasan K. Sambandamurthy

  • Article
    | Open Access

    Organometallic complexes are effective hydrogenation catalysts for organic reactions. Here the authors report for the first time that transfer hydrogenation catalysis can take place inside the cell and could be used as a novel anticancer strategy.

    • Joan J. Soldevila-Barreda
    • , Isolda Romero-Canelón
    •  & Peter J. Sadler

  • Article |

    Generating diverse structures with a minimum amount of synthetic effort is an important goal for drug discovery. Here, the authors report a two-phase synthesis for the generation of skeletally diverse small molecules—forming molecular scaffolds and subsequently diversifying each into multiple structures.

    • Miguel Garcia-Castro
    • , Lea Kremer
    •  & Kamal Kumar

  • Article
    | Open Access

    Surgical removal of the metastases remains a life-extending approach to ovarian cancer, but the nodules are difficult to detect. Here the authors show that a new cell-permeable probe for β-galactosidase can sensitively and specifically detect peritoneal metastases in mouse models of ovarian cancer.

    • Daisuke Asanuma
    • , Masayo Sakabe
    •  & Yasuteru Urano

  • Article
    | Open Access

    The study of HIV proteolysis during maturation and replication can be difficult since different steps in these processes occur simultaneously. Here, the authors present a photolabile HIV protease inhibitor which can be deactivated by light irradiation, allowing synchronized induction of viral maturation.

    • Jiří Schimer
    • , Marcela Pávová
    •  & Jan Konvalinka

  • Article
    | Open Access

    It is unclear how ingested botulinum neurotoxin invades the host to cause illness. Here, the authors show that the toxin complex containing neurotoxin, hemagglutinin (HA), and NTNHA proteins traverses the epithelial barrier via HA-glycoprotein 2 interaction and endocytosis by Peyer’s patch microfold cells.

    • Takuhiro Matsumura
    • , Yo Sugawara
    •  & Yukako Fujinaga

  • Article |

    Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al. show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.

    • Hilary A. Kenny
    • , Madhu Lal-Nag
    •  & Ernst Lengyel

  • Article
    | Open Access

    Understanding the dynamics of enzyme-substrate complexation provides an insight into potential drugs, but intermediate states are difficult to observe experimentally. Here, the authors use simulations and machine learning to analyse the binding of transition state inhibitors to purine nucleoside phosphorylase.

    • Sergio Decherchi
    • , Anna Berteotti
    •  & Andrea Cavalli

  • Article |

    Perfluorinated organic molecules have shown many uses, including as imaging agents. Here, the authors report that fluorinated gold nanoparticles offer an effective means of mass spectrometry tissue imaging, in addition to facilitating X-ray analysis providing complementary information to mass spectral images.

    • Michael E. Kurczy
    • , Zheng-Jiang Zhu
    •  & Gary Siuzdak

  • Article |

    Increased expression of MITF transcription factor is thought to promote melanoma progression and kinase inhibitor resistance. Here Muller et al. show that MITF loss is also common in melanomas and confers kinase inhibitor resistance due to upregulation of AXL and other receptor tyrosine kinases.

    • Judith Müller
    • , Oscar Krijgsman
    •  & Daniel S. Peeper

  • Article |

    Hereditary hypertrophic cardiomyopathy (HCM) is caused by mutations in cardiomyocyte genes, such as MYBPC3. Here, the authors use virus-mediated gene therapy to correct Mycbpc3mutations in 1-day-old mice and, by administering just a single dose, prevent development of HCM over a period of 34 weeks.

    • Giulia Mearini
    • , Doreen Stimpel
    •  & Lucie Carrier

  • Article |

    It is known that some nanomaterials can exhibit enzyme-like activities, prompting interest in the novel applications this property may allow. Here, the authors show how vanadia nanowires possess glutathione peroxidase-like activity, and can effectively protect cells from oxidative damage.

    • Amit A. Vernekar
    • , Devanjan Sinha
    •  & Govindasamy Mugesh

  • Article |

    Overexpression of the FOXM1 transcription factor occurs in several cancer and correlates with poor prognoses. Here, the authors identify a novel small molecule capable of displacing FOXM1 from its DNA consensus motif in vitro, displace it from target promoters and downregulate the expression of its target genes cancer cells.

    • Michael V. Gormally
    • , Thomas S. Dexheimer
    •  & Shankar Balasubramanian

  • Article
    | Open Access

    Protein scaffolds can serve as alternatives to antibodies in a range of applications. Here, the authors report the design and development of Alphabody™, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold that the authors use to develop Alphabodies that can neutralize human IL-23 with high specificity and affinity.

    • Johan Desmet
    • , Kenneth Verstraete
    •  & Savvas N. Savvides

  • Article
    | Open Access

    Sulfonylureas are widely used anti-diabetic drugs, which promote insulin release by blocking a pancreatic ion channel. Here the authors create a photoswitchable sulfonylurea derivative and use it to control insulin release from cultured cells and isolated pancreatic islets by illumination with blue light.

    • Johannes Broichhagen
    • , Matthias Schönberger
    •  & Dirk Trauner

  • Article
    | Open Access

    Deubiquitylases (DUBs) remove ubiquitin chains from proteins. Here the authors develop a mass spectrometry-based DUB activity screen using unmodified diubiquitin isomers to characterize substrate specificity for 42 human DUBs, and assess the potency and selectivity of 11 DUB inhibitors.

    • Maria Stella Ritorto
    • , Richard Ewan
    •  & Matthias Trost

  • Article
    | Open Access

    Identifying the site where a protein binds to another molecule is an important factor for the design of therapeutics intended to prevent this interaction. Here, the authors coat protein–receptor complexes with surface-binding molecules, and determine their interacting regions using mass spectrometry.

    • Alessandra Luchini
    • , Virginia Espina
    •  & Lance A. Liotta

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