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Pharmacology & Drug Discovery

  • Open Access
    CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib
    CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib
    1. Eric Raspé (eraspe{at}ulb.ac.be)*,1,2,
    2. Katia Coulonval1,2,†,
    3. Jaime M Pita1,2,†,
    4. Sabine Paternot1,2,†,
    5. Françoise Rothé2,3,†,
    6. Laure Twyffels4,5,
    7. Sylvain Brohée2,3,
    8. Ligia Craciun6,
    9. Denis Larsimont7,
    10. Véronique Kruys4,5,
    11. Flavienne Sandras8,9,
    12. Isabelle Salmon2,8,9,
    13. Steven Van Laere10,
    14. Martine Piccart2,11,
    15. Michail Ignatiadis2,3,
    16. Christos Sotiriou (christos.sotiriou{at}bordet.be)*,2,3 and
    17. Pierre P Roger (proger{at}ulb.ac.be)*,1,2
    1. 1WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
    2. 2ULB‐Cancer Research Center (U‐CRC) Université Libre de Bruxelles, Brussels, Belgium
    3. 3Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
    4. 4Laboratoire de Biologie Moléculaire du Gène, Faculté des Sciences, Université libre de Bruxelles (ULB), Brussels, Belgium
    5. 5Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), Brussels, Belgium
    6. 6Tumor Bank of the Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
    7. 7Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
    8. 8Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
    9. 9Biobank of the Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
    10. 10Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium
    11. 11Medical Oncology Clinic, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
    1. ↵* Corresponding author. Tel: +32 2 555 41 53; E‐mail: eraspe{at}ulb.ac.be
      Corresponding author. Tel: +32 2 541 34 28; E‐mail: christos.sotiriou{at}bordet.be
      Corresponding author. Tel: +32 2 555 41 53, Fax: +32 2 555 46 55; E‐mail: proger{at}ulb.ac.be

    Biomarkers able to predict breast cancer sensitivity to the newly FDA/EMA‐approved CDK4/6 inhibitor palbociclib are still lacking. Based on the T172‐phosphorylation of CDK4 as critical to the kinase activation, an 11‐gene classifier helps to segregate cancer subtypes and predict palbociclib sensitivity.

    Synopsis

    Biomarkers able to predict breast cancer sensitivity to the newly FDA/EMA‐approved CDK4/6 inhibitor palbociclib are still lacking. Based on the T172‐phosphorylation of CDK4 as critical to the kinase activation, an 11‐gene classifier helps to segregate cancer subtypes and predict palbociclib sensitivity.

    • In frozen breast cancers samples (n = 56), three distinct CDK4 modification profiles are observed using 2D‐gel electrophoresis: profile H, preponderant presence of T172‐phosphorylated CDK4 (most luminal B and HER2‐positive cancers); profile L, minor presence of phosphorylated CDK4 (90% of lower risk luminal A tumors); profile A, no phosphorylated CDK4 despite high proliferation index (60% of triple‐negative cancers).

    • An 11‐gene classifier that correctly predicts the three CDK4 modification profiles was generated and optimized using these breast tumors.

    • In 4,000 breast cancer samples, the CDK4 modification profiles as predicted by the 11‐gene classifier are associated with subtype, grade, relapse status and risk profile.

    • The 11‐gene classifier correctly predicts the observed presence or absence of CDK4 phosphorylation in 24 out of 25 breast cancer cell lines and the observed or reported sensitivity to palbociclib in 50 out of 52 breast cancer cell lines.

    • Once transposed to a qPCR assay compatible with formalin‐fixed breast tumor samples, this classifier should predict the potential sensitivity or resistance to CDK4 inhibitors and the risk and grade of tumors.

    • CDK4/6 inhibitors
    • breast cancer
    • cyclin‐dependent kinase 4
    • PD0332991
    • sensitivity biomarker

    EMBO Mol Med (2017) 9: 1052–1066

    • Received September 19, 2016.
    • Revision received May 5, 2017.
    • Accepted May 9, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Eric Raspé, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Christos Sotiriou, Pierre P Roger
    Published online 01.08.2017
  • Open Access
    γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct
    γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct
    1. Yong Ran (yran{at}ufl.edu)*,1,
    2. Fokhrul Hossain2,
    3. Antonio Pannuti2,
    4. Christian B Lessard1,
    5. Gabriela Z Ladd3,
    6. Joo In Jung1,
    7. Lisa M Minter4,
    8. Barbara A Osborne4,
    9. Lucio Miele2 and
    10. Todd E Golde (tgolde{at}ufl.edu)*,1
    1. 1Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
    2. 2Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
    3. 3College of Pharmacy, University of Florida, Gainesville, FL, USA
    4. 4Department of Veterinary and Animal Sciences and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA
    1. ↵* Corresponding author. Tel: +1 352 273 9458; Fax: +1 352 294 5060; E‐mail: yran{at}ufl.edu
      Corresponding author. Tel: +1 352 273 9458; Fax: +1 352 294 5060; E‐mail: tgolde{at}ufl.edu

    γ‐Secretase inhibitors (GSIs) have been repurposed to treat various human cancers. Using newly developed γ‐secretase cleavage assays and a breast cancer cell mammosphere inhibition assay, this study demonstrates that four clinical GSIs are neither pharmacologically nor functionally equivalent.

    Synopsis

    γ‐Secretase inhibitors (GSIs) have been repurposed to treat various human cancers. Using newly developed γ‐secretase cleavage assays and a breast cancer cell mammosphere inhibition assay, this study demonstrates that four clinical GSIs are neither pharmacologically nor functionally equivalent.

    • In vitro and cell‐based assays for human NOTCH1–4 proteins enable facile study of γ‐secretase cleavage and the effects of GSIs, as well as establish sites of cleavage.

    • Dose–response studies with clinical GSIs reveal markedly different pharmacologic properties.

    • Studies in triple‐negative breast cancer cell lines show that the clinical GSIs are functionally distinct.

    • Uncertainty remains regarding the properties of a GSI that are associated with potency in the mammosphere inhibition assay, and might be predictive of a therapeutic effect in human cancer.

    • cancer therapy
    • NOTCH
    • γ‐secretase inhibitors

    EMBO Mol Med (2017) 9: 950–966

    • Received October 27, 2016.
    • Revision received April 24, 2017.
    • Accepted April 25, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Yong Ran, Fokhrul Hossain, Antonio Pannuti, Christian B Lessard, Gabriela Z Ladd, Joo In Jung, Lisa M Minter, Barbara A Osborne, Lucio Miele, Todd E Golde
    Published online 01.07.2017
  • Open Access
    A clinical and mechanistic study of topical borneol‐induced analgesia
    A clinical and mechanistic study of topical borneol‐induced analgesia
    1. Shu Wang (wangshu{at}mail.kiz.ac.cn) (shu_wang{at}outlook.com)*,1,2,†,
    2. Dan Zhang3,†,
    3. Jinsheng Hu1,2,†,
    4. Qi Jia3,†,
    5. Wei Xu3,
    6. Deyuan Su1,2,
    7. Hualing Song4,
    8. Zhichun Xu1,2,
    9. Jianmin Cui1,5,
    10. Ming Zhou1,6,
    11. Jian Yang (jy160{at}columbia.edu) (jianyang{at}mail.kiz.ac.cn)*,1,7 and
    12. Jianru Xiao (jianruxiao83{at}163.com)*,3
    1. 1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
    2. 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China
    3. 3Department of Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
    4. 4Department of Preventive Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
    5. 5Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, USA
    6. 6Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
    7. 7Department of Biological Sciences, Columbia University, New York, NY, USA
    1. ↵* Corresponding author. Tel: +86 0871 65189257; E‐mail: wangshu{at}mail.kiz.ac.cn or shu_wang{at}outlook.com
      Corresponding author. Tel: +1 212 8546161; E‐mail: jy160{at}columbia.edu or jianyang{at}mail.kiz.ac.cn
      Corresponding author. Tel: +86 021 81886843; E‐mail: jianruxiao83{at}163.com

    1. ↵† These authors contributed equally to this work

    Borneol has been used as a topical analgesic in traditional Chinese medicine for millennia. Topical application of borneol leads to significant pain relief in humans and mouse models. The TRPM8 channel is identified as a molecular target of borneol and mediates borneol‐induced analgesia.

    Synopsis

    Borneol has been used as a topical analgesic in traditional Chinese medicine for millennia. Topical application of borneol leads to significant pain relief in humans and mouse models. The TRPM8 channel is identified as a molecular target of borneol and mediates borneol‐induced analgesia.

    • Topical application of borneol leads to significantly greater pain relief than placebo does in a randomized, double‐blind, placebo‐controlled clinical study involving 122 patients with postoperative pain.

    • The TRPM8 channel is a molecular target of borneol and mediates topical borneol‐induced analgesia in mice.

    • A downstream glutamatergic mechanism in the spinal cord contributes to topical borneol‐induced analgesia.

    • Borneol shows mechanistic differences and advantages as a topical analgesic when compared with menthol.

    • borneol
    • pain
    • topical analgesic
    • traditional Chinese medicine
    • TRPM8

    EMBO Mol Med (2017) 9: 802–815

    • Received November 6, 2016.
    • Revision received March 3, 2017.
    • Accepted March 8, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Shu Wang, Dan Zhang, Jinsheng Hu, Qi Jia, Wei Xu, Deyuan Su, Hualing Song, Zhichun Xu, Jianmin Cui, Ming Zhou, Jian Yang, Jianru Xiao
    Published online 01.06.2017
  • Open Access
    Ferrochelatase is a therapeutic target for ocular neovascularization
    Ferrochelatase is a therapeutic target for ocular neovascularization
    1. Halesha D Basavarajappa1,2,
    2. Rania S Sulaiman1,3,4,
    3. Xiaoping Qi1,
    4. Trupti Shetty1,3,
    5. Sardar Sheik Pran Babu1,
    6. Kamakshi L Sishtla1,
    7. Bit Lee5,
    8. Judith Quigley1,
    9. Sameerah Alkhairy1,
    10. Christian M Briggs1,
    11. Kamna Gupta1,
    12. Buyun Tang2,
    13. Mehdi Shadmand1,
    14. Maria B Grant1,3,
    15. Michael E Boulton1,
    16. Seung‐Yong Seo5 and
    17. Timothy W Corson (tcorson{at}iu.edu)*,1,2,3
    1. 1Eugene and Marilyn Glick Eye Institute and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA
    2. 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
    3. 3Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
    4. 4Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
    5. 5College of Pharmacy, Gachon University, Incheon, South Korea
    1. ↵*Corresponding author. Tel: +1 317 274 3305; E‐mail: tcorson{at}iu.edu

    New drug targets are needed for blocking pathological blood vessel growth in the eye in diseases such as wet age‐related macular degeneration. The heme synthesis enzyme ferrochelatase is necessary for this process and can be inhibited with therapeutic effect.

    Synopsis

    New drug targets are needed for blocking pathological blood vessel growth in the eye in diseases such as wet age‐related macular degeneration. The heme synthesis enzyme ferrochelatase is necessary for this process and can be inhibited with therapeutic effect.

    • Ferrochelatase is a target of the antiangiogenic natural product cremastranone.

    • Loss or inhibition of ferrochelatase reduces ocular neovascularization in vitro and in vivo by reducing heme needed for endothelial nitric oxide synthase function.

    • Human and murine eyes undergoing neovascularization upregulate ferrochelatase.

    • The approved drug griseofulvin, which inhibits ferrochelatase as an off‐target effect, is an effective therapy in a preclinical choroidal neovascularization model.

    • age‐related macular degeneration
    • angiogenesis
    • ferrochelatase
    • griseofulvin
    • heme synthesis

    EMBO Mol Med (2017) 9: 786–801

    • Received April 29, 2016.
    • Revision received March 1, 2017.
    • Accepted March 3, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Halesha D Basavarajappa, Rania S Sulaiman, Xiaoping Qi, Trupti Shetty, Sardar Sheik Pran Babu, Kamakshi L Sishtla, Bit Lee, Judith Quigley, Sameerah Alkhairy, Christian M Briggs, Kamna Gupta, Buyun Tang, Mehdi Shadmand, Maria B Grant, Michael E Boulton, Seung‐Yong Seo, Timothy W Corson
    Published online 01.06.2017
  • Open Access
    An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice
    An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice
    1. Yu‐Sung Cheng1,†,
    2. Zih‐ten Chen2,†,
    3. Tai‐Yan Liao2,
    4. Chen Lin2,
    5. Howard C‐H Shen2,
    6. Ya‐Han Wang2,3,
    7. Chi‐Wei Chang4,
    8. Ren‐Shyan Liu4,5,
    9. Rita P‐Y Chen (pyc{at}gate.sinica.edu.tw)*,2,3 and
    10. Pang‐hsien Tu (benrosetu{at}yahoo.com)*,1
    1. 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    2. 2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
    3. 3Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
    4. 4Biomedical Imaging Research Center, Department of Nuclear Medicine, National Yang‐Ming University and Taipei Veterans General Hospital, Taipei, Taiwan
    5. 5Molecular and Genetic Imaging Core, Taiwan Mouse Clinic, Academia Sinica, Taipei, Taiwan
    1. ↵* Corresponding author. Tel: +886 2 27855696; Fax: +886 2 27889759; E‐mail: pyc{at}gate.sinica.edu.tw
      Corresponding author. Tel: +886 2 26523532; Fax: +886 2 27827654; E‐mail: benrosetu{at}yahoo.com

    1. ↵† These authors contributed equally to this work

    Intranasal administration of an amyloid inhibitor peptide to Alzheimer transgenic mice reduces amyloid brain deposition in the brain and ameliorates cognitive decline.

    Synopsis

    Intranasal administration of an amyloid inhibitor peptide to Alzheimer transgenic mice reduces amyloid brain deposition in the brain and ameliorates cognitive decline.

    • A peptide, R8‐Aβ(25–35), combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed.

    • Daily intranasal administration of the PEI‐conjugated R8‐Aβ(25–35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery.

    • The modular design combining polyR and aggregate‐forming segments could be easily extended to other proteinaceous aggregate‐associated diseases.

    • Aβ
    • Alzheimer disease
    • peptide therapy
    • polyarginine
    • polyethylenimine

    EMBO Mol Med (2017) 9: 703–715

    • Received June 3, 2016.
    • Revision received March 1, 2017.
    • Accepted March 3, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Yu‐Sung Cheng, Zih‐ten Chen, Tai‐Yan Liao, Chen Lin, Howard C‐H Shen, Ya‐Han Wang, Chi‐Wei Chang, Ren‐Shyan Liu, Rita P‐Y Chen, Pang‐hsien Tu
    Published online 01.05.2017
  • Open Access
    Delivery is key: lessons learnt from developing splice‐switching antisense therapies
    Delivery is key: lessons learnt from developing splice‐switching antisense therapies
    1. Caroline Godfrey1,
    2. Lourdes R Desviat2,
    3. Bård Smedsrød3,
    4. France Piétri‐Rouxel4,
    5. Michela A Denti5,
    6. Petra Disterer6,
    7. Stéphanie Lorain4,
    8. Gisela Nogales‐Gadea7,
    9. Valentina Sardone8,
    10. Rayan Anwar9,10,
    11. Samir EL Andaloussi1,11,
    12. Taavi Lehto11,12,
    13. Bernard Khoo13,
    14. Camilla Brolin14,
    15. Willeke MC van Roon‐Mom15,
    16. Aurélie Goyenvalle16,
    17. Annemieke Aartsma‐Rus15 and
    18. Virginia Arechavala‐Gomeza (virginia.arechavalagomeza{at}osakidetza.eus)*,17
    1. 1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
    2. 2Centro de Biología Molecular Severo Ochoa UAM‐CSIC, CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
    3. 3Department of Medical Biology, University of Tromsø, Tromsø, Norway
    4. 4UPMC, INSERM, UMRS 974, CNRS FRE 3617, Institut de Myologie, Paris, France
    5. 5Centre for Integrative Biology, University of Trento, Trento, Italy
    6. 6Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK
    7. 7Grup d'Investigació en Malalties Neuromusculars i Neuropediatriques, Institut d' Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona Barcelona, Spain
    8. 8Dubowitz Neuromuscular Centre and Developmental Neuroscience Programme, Institute of Child Health, University College London, London, UK
    9. 9Drug Discovery Informatics Lab, Qasemi‐Research Center, Al‐Qasemi Academic College, Baka El‐Garbiah, Israel
    10. 10Drug Discovery and Development Laboratory, Institute of Applied Research, Galilee Society, Shefa‐Amr, Israel
    11. 11Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
    12. 12Institute of Technology, University of Tartu, Tartu, Estonia
    13. 13Centre for Neuroendocrinology, Division of Medicine, University College London, London, UK
    14. 14Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
    15. 15Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
    16. 16INSERM U1179, UFR des sciences de la santé, Université Versailles Saint Quentin, Montigny‐le‐Bretonneux, France
    17. 17Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo Bizkaia, Spain
    1. ↵*Corresponding author. Tel: +34 946007967; E‐mail: virginia.arechavalagomeza{at}osakidetza.eus

    The use of splice‐switching antisense therapy is promising; nevertheless, its potential to treat a variety of disorders has yet to be realized. This review discusses successes and obstacles of this approach and provides a forward look into wider application of therapeutic antisense oligonucleotides.

    • antisense oligonucleotides
    • delivery
    • pre‐clinical models
    • RNA therapy
    • toxicity

    EMBO Mol Med (2017) 9: 545–557

    • Received October 14, 2016.
    • Revision received December 15, 2016.
    • Accepted February 13, 2017.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Caroline Godfrey, Lourdes R Desviat, Bård Smedsrød, France Piétri‐Rouxel, Michela A Denti, Petra Disterer, Stéphanie Lorain, Gisela Nogales‐Gadea, Valentina Sardone, Rayan Anwar, Samir EL Andaloussi, Taavi Lehto, Bernard Khoo, Camilla Brolin, Willeke MC van Roon‐Mom, Aurélie Goyenvalle, Annemieke Aartsma‐Rus, Virginia Arechavala‐Gomeza
    Published online 01.05.2017
  • Open Access
    Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis
    Targeting <em>Toxoplasma gondii </em>CPSF3 as a new approach to control toxoplasmosis
    1. Andrés Palencia (andres.palencia{at}univ-grenoble-alpes.fr)*,1,2,†,
    2. Alexandre Bougdour (alexandre.bougdour{at}univ-grenoble-alpes.fr)*,1,†,
    3. Marie‐Pierre Brenier‐Pinchart1,
    4. Bastien Touquet1,
    5. Rose‐Laurence Bertini1,
    6. Cristina Sensi2,
    7. Gabrielle Gay1,
    8. Julien Vollaire3,
    9. Véronique Josserand3,
    10. Eric Easom4,
    11. Yvonne R Freund4,
    12. Hervé Pelloux1,
    13. Philip J Rosenthal5,
    14. Stephen Cusack2 and
    15. Mohamed‐Ali Hakimi (mohamed-ali.hakimi{at}univ-grenoble-alpes.fr)*,1
    1. 1Institute for Advanced Biosciences (IAB), Team Host‐Pathogen Interactions & Immunity to Infection, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
    2. 2European Molecular Biology Laboratory (EMBL), Grenoble Outstation and Unit of Virus Host‐Cell Interactions, University of Grenoble‐EMBL‐Centre National de la Recherche Scientifique, Grenoble Cedex 9, France
    3. 3Institute for Advanced Biosciences (IAB), OPTIMAL Small Animal Imaging Facility, Grenoble, France
    4. 4Anacor Pharmaceuticals Inc., Palo Alto, CA, USA
    5. 5Department of Medicine, University of California, San Francisco, CA, USA
    1. ↵* Corresponding author. Tel: +33 476 63 71 09; andres.palencia{at}univ-grenoble-alpes.fr
      Corresponding author. Tel: +33 476 63 71 14; alexandre.bougdour{at}univ-grenoble-alpes.fr
      Corresponding author. Tel: +33 476 63 74 69; mohamed-ali.hakimi{at}univ-grenoble-alpes.fr

    1. ↵† These authors contributed equally to this work

    Benzoxaboroles are boron‐containing compounds effective against a wide range of infectious pathogens. The benzoxaborole AN3661 is a novel drug candidate against acute toxoplasmosis. The compound blocks an unprecedented target of Toxoplasma, the endonuclease CPSF3 that cleaves 3′‐mRNAs in eukaryotes.

    Synopsis

    Benzoxaboroles are boron‐containing compounds effective against a wide range of infectious pathogens. The benzoxaborole AN3661 is a novel drug candidate against acute toxoplasmosis. The compound blocks an unprecedented target of Toxoplasma, the endonuclease CPSF3 that cleaves 3′‐mRNAs in eukaryotes.

    • AN3661 inhibits Toxoplasma growth in vitro at low micromolar concentrations, with potency comparable to that of the clinically relevant drug pyrimethamine.

    • AN3661 orally administered to mice controls otherwise lethal infections with comparable efficacy to sulfadiazine, the standard of care to treat toxoplasmosis.

    • Mice treated with AN3661 developed protective immunity to subsequent Toxoplasma infections.

    • Forward genetics and CRISPR/Cas9 editing validated CPSF3 as the main target of AN3661 in Toxoplasma.

    • Structural modelling allowed to place the resistant mutations at the Toxoplasma CPSF3 catalytic site and to identify the putative binding site of AN3661.

    • benzoxaborole
    • CPSF3
    • drug discovery
    • mRNA processing
    • Toxoplasma gondii
    • toxoplasmosis

    EMBO Mol Med (2017) 9: 385–394

    • Received November 22, 2016.
    • Accepted December 22, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Andrés Palencia, Alexandre Bougdour, Marie‐Pierre Brenier‐Pinchart, Bastien Touquet, Rose‐Laurence Bertini, Cristina Sensi, Gabrielle Gay, Julien Vollaire, Véronique Josserand, Eric Easom, Yvonne R Freund, Hervé Pelloux, Philip J Rosenthal, Stephen Cusack, Mohamed‐Ali Hakimi
    Published online 01.03.2017
  • Open Access
    PERK activation mitigates tau pathology in vitro and in vivo
    PERK activation mitigates tau pathology <em>in vitro</em> and <em>in vivo</em>
    1. Julius Bruch1,2,3,†,
    2. Hong Xu1,2,3,†,
    3. Thomas W Rösler1,2,†,
    4. Anderson De Andrade1,3,
    5. Peer‐Hendrik Kuhn4,5,
    6. Stefan F Lichtenthaler3,4,6,
    7. Thomas Arzberger7,
    8. Konstanze F Winklhofer3,8,
    9. Ulrich Müller9 and
    10. Günter U Höglinger (guenter.hoeglinger{at}dzne.de)*,1,2,3
    1. 1Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    2. 2Department of Neurology, Technical University of Munich (TUM), Munich, Germany
    3. 3Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
    4. 4Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich (TUM), Munich, Germany
    5. 5Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
    6. 6Neuroproteomics, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    7. 7Center for Neuropathology and Prion Research (ZNP), University of Munich, Munich, Germany
    8. 8Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University, Bochum, Germany
    9. 9Institute for Human Genetics, University of Giessen, Giessen, Germany
    1. ↵*Corresponding author. Tel: +49 89 4400 46464; E‐mail: guenter.hoeglinger{at}dzne.de

    1. ↵† These authors contributed equally to this work

    A polymorphism in the RNA‐like endoplasmic reticulum kinase (PERK) gene was tightly associated with the tauopathy progressive supranuclear palsy (PSP). The present work explores the function of PERK in tauopathy models and found that PERK activation may be a novel therapeutic strategy for tauopathies.

    Synopsis

    A polymorphism in the RNA‐like endoplasmic reticulum kinase (PERK) gene was tightly associated with the tauopathy progressive supranuclear palsy (PSP). The present work explores the function of PERK in tauopathy models and found that PERK activation may be a novel therapeutic strategy for tauopathies.

    • PERK activation reduced tau phosphorylation, tau conformational change, and 4‐repeat tau isoforms and increased cell viability in cultured human neurons.

    • PERK activation improved memory and locomotor functions, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice.

    • The PERK substrate EIF2A was downregulated in PSP brains and in tauopathy models.

    • The PERK substrate NRF2 appears to account for the beneficial effects in the context of tauopathies.

    • EIF2A
    • NRF2
    • PERK
    • progressive supranuclear palsy
    • tauopathy

    EMBO Mol Med (2017) 9: 371–384

    • Received June 6, 2016.
    • Revision received December 22, 2016.
    • Accepted December 23, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Julius Bruch, Hong Xu, Thomas W Rösler, Anderson De Andrade, Peer‐Hendrik Kuhn, Stefan F Lichtenthaler, Thomas Arzberger, Konstanze F Winklhofer, Ulrich Müller, Günter U Höglinger
    Published online 01.03.2017
  • Open Access
    How to tackle antimalarial resistance?
    How to tackle antimalarial resistance?
    1. Didier Leroy (leroyd{at}mmv.org)1
    1. 1Medicines for Malaria Venture, Geneva, Switzerland

    In the context of drug resistance, malaria is no exception. Even the latest artemisinins have started to lose their full efficacy in patients. Didier Leroy tells us about the strategies adopted by Medicines for Malaria Venture to reduce this terrible culprit.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Didier Leroy
    Published online 01.02.2017
  • Open Access
    Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina
    Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina
    1. Marcus Karlstetter1,2,
    2. Jens Kopatz3,
    3. Alexander Aslanidis1,
    4. Anahita Shahraz3,
    5. Albert Caramoy1,
    6. Bettina Linnartz‐Gerlach3,
    7. Yuchen Lin4,
    8. Anika Lückoff1,
    9. Sascha Fauser1,
    10. Katharina Düker3,
    11. Janine Claude3,
    12. Yiner Wang3,
    13. Johannes Ackermann3,
    14. Tobias Schmidt5,
    15. Veit Hornung5,6,
    16. Christine Skerka4,
    17. Thomas Langmann (thomas.langmann{at}uk-koeln.de)*,1,† and
    18. Harald Neumann (hneuman1{at}uni-bonn.de)*,3,†
    1. 1Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
    2. 2Therapeutic Research Group Ophthalmology, Bayer Pharma AG, Wuppertal, Germany
    3. 3Institute of Reconstructive Neurobiology, University Hospital Bonn, University of Bonn, Bonn, Germany
    4. 4Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
    5. 5Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany
    6. 6Gene Center and Department of Biochemistry, Ludwig‐Maximilians‐Universität München, Munich, Germany
    1. ↵* Corresponding author. Tel: +49 221 478 7324; E‐mail: thomas.langmann{at}uk-koeln.de
      Corresponding author. Tel: +49 228 6885 541; E‐mail: hneuman1{at}uni-bonn.de

    1. ↵† These authors contributed equally to this work

    Low molecular weight polysialic acid (polySia avDP20) ameliorates laser‐induced inflammation and choroidal neovascularization in a humanized mouse model of AMD‐like laser‐induced retinal injury.

    Synopsis

    Low molecular weight polysialic acid (polySia avDP20) ameliorates laser‐induced inflammation and choroidal neovascularization in a humanized mouse model of AMD‐like laser‐induced retinal injury.

    • Low‐dose polySia avDP20 reduces reactivity of mononuclear phagocytes and vascular leakage induced by laser coagulation in humanized transgenic mice expressing sialic acid‐binding immunoglobulin‐like lectin‐11 (SIGLEC11).

    • PolySia avDP20 prevents deposition of the membrane attack complex in both SIGLEC11 transgenic and wild‐type mouse retinal pigment epithelium/choroids.

    • PolySia avDP20 prevents tumor necrosis factor‐α, vascular endothelial growth factor A, and superoxide production of cultured SIGLEC11‐positive phagocytes.

    • PolySia avDP20 directly interferes with complement activation in vitro.

    • age‐related macular degeneration
    • complement
    • microglia
    • polysialic acid
    • SIGLEC

    EMBO Mol Med (2017) 9: 154–166

    • Received May 24, 2016.
    • Revision received November 21, 2016.
    • Accepted November 22, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Marcus Karlstetter, Jens Kopatz, Alexander Aslanidis, Anahita Shahraz, Albert Caramoy, Bettina Linnartz‐Gerlach, Yuchen Lin, Anika Lückoff, Sascha Fauser, Katharina Düker, Janine Claude, Yiner Wang, Johannes Ackermann, Tobias Schmidt, Veit Hornung, Christine Skerka, Thomas Langmann, Harald Neumann
    Published online 01.02.2017

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