Medicinal chemistry articles within Nature Communications

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  • Article
    | Open Access

    Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.

    • David A. Baker
    • , Lindsay B. Stewart
    •  & Simon A. Osborne

  • 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

    PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.

    • Elena Campaner
    • , Alessandra Rustighi
    •  & Giannino Del Sal

  • Article
    | Open Access

    Epigenetic drugs are emerging as a powerful therapeutic option for cancer treatment. Here, the authors synthesized selective chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity and demonstrate their anti-tumour activity usingin vitro and in vivomodels of haematological neoplasia.

    • Edurne San José-Enériz
    • , Xabier Agirre
    •  & Felipe Prosper

  • Article
    | Open Access

    Heterocycles are ubiquitous in bioactive compounds and routes to different substitution patterns are important to access the full substrate space. Here the authors report a route to 4,5,7,8-substituted antiviral fluorescent quinazolines, to allow cellular uptake visualization without external marker.

    • Felix E. Held
    • , Anton A. Guryev
    •  & Svetlana B. Tsogoeva

  • 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

    Allostery and drug-drug synergism can yield potential novel therapies with existing molecules. Here, the authors provide evidence that two unrelated drugs have increased cytotoxicity in cancer cells, which coincides with increased formation of chromatin adducts.

    • Zenita Adhireksan
    • , Giulia Palermo
    •  & Curt A. Davey

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Drug resistant tuberculosis (TB) infections are emerging at a high rate, with only few therapeutic options currently available. Here, the authors report synthetic analogues of the natural product sansanmycin that target mycobacterial cell wall biosynthesis and represent potent leads for improved anti-TB treatments.

    • Anh T. Tran
    • , Emma E. Watson
    •  & Richard J. Payne

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Small molecule probes used to trigger hypoxic response by activating hypoxia inducible factors (HIFs) often lack specificity. Here the authors report a potent small molecule inhibitor that induces hypoxic response by blocking VHL:HIF interactions, providing a selective route to probe hypoxic signalling.

    • Julianty Frost
    • , Carles Galdeano
    •  & Alessio Ciulli

  • Article
    | Open Access

    Nanomedicine efficacy in a clinical setting depends on the pharmacological properties of the therapeutic nanoparticles. Here, the authors exemplify an accelerated translational strategy from small-scale screening to clinical scale-up for an orally-dosed aqueous paediatric HIV nanomedicine.

    • Marco Giardiello
    • , Neill J. Liptrott
    •  & Andrew Owen

  • Article
    | Open Access

    Reversible manipulation of cell-cell interactions has potential applications in basic research and cell-based therapy. Here the authors control cell-cell adhesion in vitrowith light, by modifying the surface sugars of cells to display β-cyclodextrin, which recognises one isoform of light-isomerizable azobenzene linkers.

    • Peng Shi
    • , Enguo Ju
    •  & Xiaogang Qu

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Deoxyelephantopin is a naturally occurring sesquiterpene lactone with known anticancer properties. Here, the authors synthesize deoxyelephantopins and a range of analogues including alkyne-tagged probes, using them to identify its cellular targets.

    • Roman Lagoutte
    • , Christelle Serba
    •  & Nicolas Winssinger

  • Article
    | Open Access

    Teixobactin is a recently identified antibiotic that shows activity against drug resistant strains of bacteria. Here, the authors report a highly convergent total synthesis of this natural product, with sufficient flexibility to also allow the synthesis of a number of analogues.

    • Kang Jin
    • , Iek Hou Sam
    •  & Xuechen Li

  • Article
    | Open Access

    G protein-coupled receptors (GPCRs) are involved in key signalling pathways and represent important targets for the treatment of neurological and psychiatric disorders. Here, the authors describe powerful bivalent ligands that efficiently bind to therapeutically relevant GPCR heterodimers

    • Harald Hübner
    • , Tamara Schellhorn
    •  & Peter Gmeiner

  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • 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

    Flexible electronics promise the opportunity to monitor biological activity via implanted devices. Here, the authors develop a biocompatible conductive carbon nanotube/gel composite and couple it with an ultrathin flexible amplifier, enabling in vivomeasurement of epicardial electrocardiogram signals.

    • Tsuyoshi Sekitani
    • , Tomoyuki Yokota
    •  & Takao Someya

  • 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

    Bicyclic peptides can inhibit biological targets hard to address with small molecules. Here, the authors combine two orthogonal ring-closing reactions to produce bicyclic peptides with improved bioactivity thereby providing a strategy that can greatly improve the structural diversity of such peptides.

    • Philipp M. Cromm
    • , Sebastian Schaubach
    •  & Herbert Waldmann

  • 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

    Real time cellular fluorescence imaging requires a probe that displays high degrees of localisation, low toxicity and good photostability. Here, the authors report a near infrared fluorophore that displays pH-sensitive fluorescence based on phenol/phenolate interconversion, showing real time imaging of cellular processes.

    • Marco Grossi
    • , Marina Morgunova
    •  & Donal F. O’Shea

  • Article
    | Open Access

    The conformational dynamics of a compound has a large effect on ligand/receptor binding. Here, the authors employ NMR spectroscopy to study ligand binding to the enzyme LpxC, discovering an inhibitor envelope that was not identifiable by crystallography and subsequently developing a highly potent inhibitor.

    • Chul-Jin Lee
    • , Xiaofei Liang
    •  & Pei Zhou

  • 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

    Drug molecules operate through physical interaction with specific cellular targets, and understanding this interaction is important for mechanisms and the potential therapeutic effect of drug candidates. Here, the authors show that bioluminescence resonance energy transfer can be used to monitor the intracellular engagement of a drug with its target.

    • Matthew B. Robers
    • , Melanie L. Dart
    •  & Keith V. Wood

  • 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

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