Repurposing Fragile X Drugs to Inhibit SARS-CoV-2 Viral Reproduction

The COVID-19 pandemic is a global health crisis that requires the application of interdisciplinary research to address numerous knowledge gaps including molecular strategies to prevent viral reproduction in affected individuals. In response to the Frontiers Research Topic, “Coronavirus disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management, and Public Health Response,” this Hypothesis article proposes a novel therapeutic strategy to repurpose metabotropic glutamate 5 receptor (mGluR5) inhibitors to interfere with viral hijacking of the host protein synthesis machinery. We review pertinent background on SARS-CoV-2, fragile X syndrome (FXS) and metabotropic glutamate receptor 5 (mGluR5) and provide a mechanistic-based hypothesis and preliminary data to support testing mGluR5 inhibitors in COVID-19 research.

[1]  J. Wilusz,et al.  The interface between coronaviruses and host cell RNA biology: Novel potential insights for future therapeutic intervention , 2020, Wiley interdisciplinary reviews. RNA.

[2]  M. Ahmadian,et al.  Novel FMRP interaction networks linked to cellular stress , 2020, The FEBS journal.

[3]  Jiahua He,et al.  Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2 , 2020, Viruses.

[4]  Jon Cohen,et al.  Race to find COVID-19 treatments accelerates. , 2020, Science.

[5]  S. Opal,et al.  Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection , 2020, mBio.

[6]  L. Berthoux.  The Restrictome of Flaviviruses , 2020, Virologica Sinica.

[7]  G. Bassell,et al.  Regulation of RNA granules by FMRP and implications for neurological diseases , 2020, Traffic.

[8]  Immune-mediated , 2020, Definitions.

[9]  Ralph S. Baric,et al.  Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus , 2020, Journal of Virology.

[10]  G. Gao,et al.  A Novel Coronavirus from Patients with Pneumonia in China, 2019 , 2020, The New England journal of medicine.

[11]  J. Taube,et al.  Lipopolysaccharide-induced inflammation leads to acute elevations in pro-inflammatory cytokine expression in a mouse model of Fragile X syndrome , 2019, Physiology & Behavior.

[12]  N. Glaichenhaus,et al.  Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome , 2019, BMC Neurology.

[13]  Kathe P. Fox,et al.  The phenotypical implications of immune dysregulation in fragile X syndrome , 2019, European journal of neurology.

[14]  D. J. Doty,et al.  Positive modulation of mGluR5 attenuates seizures and reduces TNF-α+ macrophages and microglia in the brain in a murine model of virus-induced temporal lobe epilepsy , 2019, Experimental Neurology.

[15]  M. Garcia-Blanco,et al.  Fragile X mental retardation protein is a Zika virus restriction factor that is antagonized by subgenomic flaviviral RNA , 2018, eLife.

[16]  Laurent Chatel-Chaix,et al.  The Multiples Fates of the Flavivirus RNA Genome During Pathogenesis , 2018, Front. Genet..

[17]  Mark F. Bear,et al.  Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome , 2017, Nature Reviews Drug Discovery.

[18]  A. Rotenberg,et al.  mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex , 2017, Neuropsychopharmacology.

[19]  W. Grueber,et al.  A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells , 2017, The Journal of cell biology.

[20]  M. Bear,et al.  Fragile X Syndrome From Genetics to Targeted Treatment , 2017 .

[21]  Mark Wakefield,et al.  A Phase 2A Trial of the Novel mGluR5‐Negative Allosteric Modulator Dipraglurant for Levodopa‐Induced Dyskinesia in Parkinson's Disease , 2016, Movement disorders : official journal of the Movement Disorder Society.

[22]  I. Brierley,et al.  High-Resolution Analysis of Coronavirus Gene Expression by RNA Sequencing and Ribosome Profiling , 2016, PLoS pathogens.

[23]  S. Perlman,et al.  Coronaviruses: An Overview of Their Replication and Pathogenesis , 2015, Methods in molecular biology.

[24]  J. Wettstein,et al.  Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome. , 2015, Current opinion in pharmacology.

[25]  F. Tassone,et al.  Immune mediated disorders in women with a fragile X expansion and FXTAS , 2015, American journal of medical genetics. Part A.

[26]  Ewa Gutmajster,et al.  Anti-Neuronal Antibodies in Patients with Fragile X Syndrome: Is there a Role of Autoimmunity in Its Pathogenesis? , 2014, Neurodegenerative Diseases.

[27]  Fang Li,et al.  Receptor Recognition Mechanisms of Coronaviruses: a Decade of Structural Studies , 2014, Journal of Virology.

[28]  F. Tassone,et al.  Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome , 2014, Journal of Neuroinflammation.

[29]  F. Tassone,et al.  Immune Dysregulation as a Cause of Autoinflammation in Fragile X Premutation Carriers: Link between FMRI CGG Repeat Number and Decreased Cytokine Responses , 2014, PloS one.

[30]  Petr Klus,et al.  catRAPID omics: a web server for large-scale prediction of protein–RNA interactions , 2013, Bioinform..

[31]  Petr Klus,et al.  Neurodegenerative diseases: quantitative predictions of protein-RNA interactions. , 2013, RNA.

[32]  D. Nguyen,et al.  Immune‐mediated disorders among women carriers of fragile X premutation alleles , 2012, American journal of medical genetics. Part A.

[33]  M. Bear,et al.  Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice , 2012, Neuron.

[34]  Anil Kumar,et al.  Involvement of metabotropic glutamate receptor 5, AKT/PI3K Signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes , 2012, Journal of Neuroinflammation.

[35]  W. Spooren,et al.  CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor , 2011, Journal of Pharmacology and Experimental Therapeutics.

[36]  D. Licatalosi,et al.  FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism , 2011, Cell.

[37]  Federico Agostini,et al.  Predicting protein associations with long noncoding RNAs , 2011, Nature Methods.

[38]  M. Bear,et al.  Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome , 2010, The Journal of Neuroscience.

[39]  R. Jope,et al.  Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome. , 2010, Biochimica et biophysica acta.

[40]  D. Nguyen,et al.  Plasma cytokine profiles in Fragile X subjects: Is there a role for cytokines in the pathogenesis? , 2010, Brain, Behavior, and Immunity.

[41]  D. Brian,et al.  Subgenomic messenger RNA amplification in coronaviruses , 2010, Proceedings of the National Academy of Sciences.

[42]  Scott B. Dewell,et al.  Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP , 2010, Cell.

[43]  W. Danysz,et al.  Metabotropic glutamate receptors as therapeutic targets for cognitive disorders. , 2010, Current topics in medicinal chemistry.

[44]  M. Bear,et al.  Hypersensitivity to mGluR 5 and ERK 1 / 2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome , 2010 .

[45]  W. Greenough,et al.  From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome , 2005, Nature Reviews Neuroscience.

[46]  S. Eddy,et al.  Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. , 2005, Genes & development.

[47]  Mark F Bear,et al.  The mGluR theory of fragile X mental retardation , 2004, Trends in Neurosciences.

[48]  I. Weiler,et al.  RNA Cargoes Associating with FMRP Reveal Deficits in Cellular Functioning in Fmr1 Null Mice , 2003, Neuron.

[49]  É. Khandjian,et al.  Trapping of messenger RNA by Fragile X Mental Retardation protein into cytoplasmic granules induces translation repression. , 2002, Human molecular genetics.

[50]  J. Darnell,et al.  Microarray Identification of FMRP-Associated Brain mRNAs and Altered mRNA Translational Profiles in Fragile X Syndrome , 2001, Cell.

[51]  J. Darnell,et al.  Fragile X Mental Retardation Protein Targets G Quartet mRNAs Important for Neuronal Function , 2001, Cell.

[52]  J. Mandel,et al.  The Fragile X mental retardation protein , 2001, Brain Research Bulletin.

[53]  S. Warren,et al.  The fragile X mental retardation protein inhibits translation via interacting with mRNA. , 2001, Nucleic acids research.

[54]  A. Ostareck-Lederer,et al.  Evidence that fragile X mental retardation protein is a negative regulator of translation. , 2001, Human molecular genetics.

[55]  T. Gibson,et al.  Dissecting FMR1, the protein responsible for fragile X syndrome, in its structural and functional domains. , 1999, RNA.

[56]  D. Absher,et al.  FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. , 1997, Molecular cell.

[57]  I. Weiler,et al.  Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[58]  S. Hersch,et al.  Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes , 1997, The Journal of Neuroscience.

[59]  R. Nussbaum,et al.  Essential role for KH domains in RNA binding: Impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome , 1994, Cell.

[60]  J. Sutcliffe,et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome , 1991, Cell.