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| Open AccessFragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities
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
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Article
| Open AccessStructure-guided development of heterodimer-selective GPCR ligands
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
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| Open AccessMultiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis
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
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Article
| Open AccessDesign of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10
Expanded RNA repeats in non-coding region of a gene represent a hallmark of several diseases. Here, the authors identify two small molecules that selectively bind AU repeats and use them to design a compound that targets the pathogenic RNA associated with spinocerebellar ataxia type 10.
- Wang-Yong Yang
- , Rui Gao
- & Matthew D. Disney
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Article
| Open AccessIdentification of pyrazolopyridazinones as PDEδ inhibitors
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
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Article
| Open AccessProtein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models
Conformational plasticity influences several aspects of protein function. Here the authors combine extensive MD simulations with Markov state models—using trypsin as model—to reveal new mechanistic details of how conformational plasticity influence ligand-receptors interactions.
- Nuria Plattner
- & Frank Noé
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Article
| Open AccessStructural basis of IL-23 antagonism by an Alphabody protein scaffold
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
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Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin–neuraminidase inhibitors
Human parainfluenza viruses (hPIVs) cause common respiratory diseases in children. Here the authors rationally design small molecules targeting the hPIV haemagglutinin–neuraminidase protein, and show that the compounds inhibit viral entry and exit from cultured cells.
- Patrice Guillon
- , Larissa Dirr
- & Mark von Itzstein
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Activation pathway of Src kinase reveals intermediate states as targets for drug design
Activation of c-src kinase is associated with uncontrolled growth and metastasis of tumour cells. Shukla et al.model conformational changes in c-src during activation, and identify an allosteric site in an intermediate state that may provide a target for small molecule therapeutics.
- Diwakar Shukla
- , Yilin Meng
- & Vijay S. Pande
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Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses
Parasites such as malaria elicit an immune response in their host, causing cytokine levels to increase. In this study, a parasite housekeeping gene, tyrosyl-tRNA synthetase, is shown to bind to host macrophages and, once inside the cells, enhance the levels of proinflammatory cytokines.
- Tarun Kumar Bhatt
- , Sameena Khan
- & Amit Sharma
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Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A
The kinase Dyrk1A is essential for brain function and development, and its excessive activity has been implicated in Down syndrome. In this study, a selective inhibitor of Dyrk1A is developed, which may help to elucidate the molecular mechanisms of normal and diseased brain.
- Yasushi Ogawa
- , Yosuke Nonaka
- & Masatoshi Hagiwara