Drug discovery articles within Nature Communications

Featured

  • Article
    | Open Access

    Schistosomiasis is caused by infection with the flatworm Schistosoma, and praziquantel is the drug of choice for its treatment. Here, Chan and colleagues identify praziquantel as a ligand for the human serotoninergic 5-HT2B G-protein-coupled receptor, and reveal a function for praziquantel as a regulator of vascular tone in treated hosts.

    • John D. Chan
    • , Pauline M. Cupit
    •  & Jonathan S. Marchant

  • Article
    | Open Access

    Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.

    • Gregory Segala
    • , Marion David
    •  & Sandrine Silvente-Poirot

  • Article
    | Open Access

    Chemical screens can identify small molecules that affect biological development, with potential therapeutic value. Here, the authors use a modular approach in a screen in zebrafish embryos, varying concentration, genotype and timing to target segmentation disorders, birth defects that affect the spinal column.

    • Sandra Richter
    • , Ulrike Schulze
    •  & Andrew C. Oates

  • Article
    | Open Access

    Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an immunotherapeutic target for cancer therapy. Here, the authors present the substrate-, inhibitor- and effector-bound hIDO1 crystal structures, which give insights into the mechanism and reveal a second small molecule binding site, which is of interest for drug design.

    • Ariel Lewis-Ballester
    • , Khoa N. Pham
    •  & Syun-Ru Yeh

  • Article
    | Open Access

    ABCC4 is a chemotherapeutic drug exporter highly expressed in acute myeloid leukemia. Here, the authors demonstrate that MPP1 anchors ABCC4 to the outer cell membrane mediating drug resistance in leukemic cells and identify antimycin A as a chemical probe that disrupts such interaction and restores sensitivity.

    • Aaron Pitre
    • , Yubin Ge
    •  & John D. Schuetz

  • Article
    | Open Access

    A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.

    • Jayme L. Dahlin
    • , Kathryn M. Nelson
    •  & Michael A. Walters

  • 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

    Reengineering polyketide synthase encoding genes to produce analogues of natural products can be slow and low-yielding. Here the authors use accelerated evolution to recombine the gene cluster for rapid production of rapamycin-related products.

    • Aleksandra Wlodek
    • , Steve G. Kendrew
    •  & Matthew A. Gregory

  • Article
    | Open Access

    Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.

    • Haibin Zhou
    • , Jianfeng Lu
    •  & Shaomeng Wang

  • Article
    | Open Access

    Exon skipping is a strategy for the treatment of Duchenne muscular dystrophy, but has variable efficacy. Here, the authors show that dystrophin restoration occurs preferentially in areas of myofiber regeneration, where antisense oligonucleotides are stored in macrophages and delivered to myoblasts and newly formed myotubes

    • James S. Novak
    • , Marshall W. Hogarth
    •  & Terence A. Partridge

  • Article
    | Open Access

    The polymerase and histidinol phosphatase (PHP) domain in the DNA polymerase DnaE1 is essential for mycobacterial high-fidelity DNA replication. Here, the authors determine the DnaE1 crystal structure, which reveals the PHP-exonuclease mechanism that can be exploited for antibiotic development.

    • Soledad Baños-Mateos
    • , Anne-Marie M. van Roon
    •  & Meindert H. Lamers

  • Article
    | Open Access

    Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor β–retinoic X receptor α (RARβ–RXRα) heterodimer bound to DNA, ligands and coactivator peptides, which shows that NR quaternary architectures are variable.

    • Vikas Chandra
    • , Dalei Wu
    •  & Fraydoon Rastinejad

  • Article
    | Open Access

    Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.

    • Nicolas Bertrand
    • , Philippe Grenier
    •  & Omid C. Farokhzad

  • Article
    | Open Access

    Atypical antipsychotics show reduced extrapyramidal side effects compared to first generation drugs. Here the authors use time-resolved FRET to measure binding kinetics, and show that side effects correlate with drug association rates to the D2 receptor, while dissociation rates correlate with prolactin elevation.

    • David A. Sykes
    • , Holly Moore
    •  & Steven J. Charlton

  • Article
    | Open Access

    The xenobiotic-activated human pregnane X receptor (hPXR) regulates drug metabolism. Here the authors develop hPXR modulators, which are of potential therapeutic interest and functionally and structurally characterize the antagonist SPA70 and the structurally related agonist SJB7.

    • Wenwei Lin
    • , Yue-Ming Wang
    •  & Taosheng Chen

  • Article
    | Open Access

    Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.

    • Jessica Vincent
    • , Carolina Adura
    •  & Manuel Ascano

  • Article
    | Open Access

    Traditional approaches used in the pharmaceutical industry are not precise or versatile enough for customized medicine formulation and manufacture. Here the authors produce a method to form coatings, with accurate dosages, as well as a means of closely controlling dissolution kinetics.

    • Olga Shalev
    • , Shreya Raghavan
    •  & Max Shtein

  • 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

    The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.

    • Heike Fuhrmann-Stroissnigg
    • , Yuan Yuan Ling
    •  & Paul D. Robbins

  • Article
    | Open Access

    Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.

    • Junying Ma
    • , Hongbo Huang
    •  & Jianhua Ju

  • Article
    | Open Access

    Omecamtiv mecarbil (OM) is a cardiac myosin activator that is currently in clinical trials for heart failure treatment. Here, the authors give insights into its mode of action and present the crystal structure of OM bound to bovine cardiac myosin, which shows that OM stabilizes the pre-powerstroke state of myosin.

    • Vicente J. Planelles-Herrero
    • , James J. Hartman
    •  & Anne Houdusse

  • Article
    | Open Access

    Respiratory syncytial virus causes lung infections in children, immunocompromised adults, and in the elderly. Here the authors show that a chemical inhibitor to a viral fusion protein is effective in reducing viral titre and ameliorating infection in rodents and neonatal lambs.

    • Dirk Roymans
    • , Sarhad S Alnajjar
    •  & Anil Koul

  • 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

    Increased availability of large-scale molecular profiling has enabled system-level monitoring of molecular effects of candidate therapeutics. Here, the authors take advantage of such data to show that the ability of a drug to reverse cancer-associated gene expression changes is indicative of itsin vitroanti-proliferative efficacy, allowing them to identify novel compounds against liver cancer.

    • Bin Chen
    • , Li Ma
    •  & Atul J. Butte

  • Article
    | Open Access

    Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

    • Eunice E. To
    • , Ross Vlahos
    •  & Stavros Selemidis

  • Article
    | Open Access

    Human liver chimeric mice are increasingly used for drug testing in preclinical development, but express residual murine p450 cytochromes. Here the authors generate mice lacking the Por gene in the liver, and show that human cytochrome metabolism is used following repopulation with human hepatocytes.

    • Mercedes Barzi
    • , Francis P. Pankowicz
    •  & Karl-Dimiter Bissig

  • Article
    | Open Access

    Kynurenine-3-monooxygenase (KMO) is an emerging clinical target for treatment of neurodegenerative diseases and acute pancreatitis. Here, the authors report potent inhibitors that bind KMO in an unexpected conformation, offering structural and mechanistic insights for future drug discovery ventures.

    • Jonathan P. Hutchinson
    • , Paul Rowland
    •  & Chun-wa Chung

  • 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

    In vitroblood-brain barrier (BBB) models are crucial tools for screening brain-penetrating compounds. Here the authors develop a self-assembling BBB spheroid model with superior performance to the standard transwell BBB model, and use their platform to identify cell-penetrating peptides that can cross the BBB.

    • Choi-Fong Cho
    • , Justin M. Wolfe
    •  & Sean E. Lawler

  • 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

    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

    BET proteins bind chromatin through their bromodomains (BDs) to regulate transcription and chromatin remodelling. Here, the authors show that the BET protein Bdf1 is essential for the fungal pathogenCandida albicans, and report compounds that inhibit the Bdf1 BDs with high selectivity over human BDs.

    • Flore Mietton
    • , Elena Ferri
    •  & Carlo Petosa

  • Article
    | Open Access

    There is a need forPlasmodium transmission blocking drugs for malaria elimination. Here, Miguel-Blanco et al. screen >10,000 compounds against stage V female gametocytes, identify active compounds belonging to 57 chemotypes and confirm transmission blocking activity of four selected compounds in vitro.

    • Celia Miguel-Blanco
    • , Irene Molina
    •  & Esperanza Herreros

  • Article
    | Open Access

    Inhibition of GDF8 increases muscle mass in mice, but is less effective in monkeys and humans. Here the authors show that activin A also inhibits muscle hypertrophy and that concomitant inhibition of activin A and GDF8 synergistically increases muscle mass in mice and non-human primates.

    • Esther Latres
    • , Jason Mastaitis
    •  & Jesper Gromada

  • Article
    | Open Access

    River blindness, a disease affecting millions throughout the tropics, is caused by parasitic worms. Here, Yuet al. report the discovery and structural characterization of potent macrocyclic peptide inhibitors of iPGM, a nematode-specific phosphoglycerate mutase, as potential leads for novel antimicrobial agents.

    • Hao Yu
    • , Patricia Dranchak
    •  & James Inglese

  • Article
    | Open Access

    The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.

    • Kenneth Verstraete
    • , Frank Peelman
    •  & Savvas N. Savvides

  • 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

Browse broader subjects

Browse narrower subjects

Browse Drug discovery across other nature.com journals