Molecular Determinants of GS-9620-Dependent TLR7 Activation
GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. How...
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| Veröffentlicht in: | PloS one 2016-01, Vol.11 (1), p.e0146835-e0146835 |
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| creator | Rebbapragada, Indrani Birkus, Gabriel Perry, Jason Xing, Weimei Kwon, HyockJoo Pflanz, Stefan |
| description | GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands. |
| doi_str_mv | 10.1371/journal.pone.0146835 |
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Keith</contributor><creatorcontrib>Rebbapragada, Indrani ; Birkus, Gabriel ; Perry, Jason ; Xing, Weimei ; Kwon, HyockJoo ; Pflanz, Stefan ; Reeves, R. Keith</creatorcontrib><description>GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0146835</identifier><identifier>PMID: 26784926</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine triphosphatase ; AKT protein ; Amino Acid Sequence ; Binding Sites ; Biology ; Cell activation ; Cells, Cultured ; Chronic infection ; Dendritic cells ; Deoxyribonucleic acid ; Determinants ; DNA ; Drug resistance ; Drug therapy ; Genetic aspects ; HEK293 Cells ; Hepatitis ; Hepatitis B ; HIV infections ; Humans ; Immune system ; Immunoglobulins ; Immunology ; Ligands ; Molecular interactions ; Molecular Sequence Data ; Molecular structure ; Mutation ; NF-κB protein ; Oral administration ; Penicillin ; Physiological aspects ; Polymorphism, Single Nucleotide ; Protein Binding ; Proteins ; Pteridines - pharmacology ; Signal transduction ; Single-nucleotide polymorphism ; TLR7 protein ; Toll-Like Receptor 7 - agonists ; Toll-Like Receptor 7 - chemistry ; Toll-Like Receptor 7 - genetics ; Toll-Like Receptor 7 - metabolism ; Toll-like receptors</subject><ispartof>PloS one, 2016-01, Vol.11 (1), p.e0146835-e0146835</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Rebbapragada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands.</description><subject>Adenosine triphosphatase</subject><subject>AKT protein</subject><subject>Amino Acid Sequence</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Chronic infection</subject><subject>Dendritic cells</subject><subject>Deoxyribonucleic acid</subject><subject>Determinants</subject><subject>DNA</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>Genetic aspects</subject><subject>HEK293 Cells</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>HIV infections</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Ligands</subject><subject>Molecular interactions</subject><subject>Molecular Sequence Data</subject><subject>Molecular structure</subject><subject>Mutation</subject><subject>NF-κB protein</subject><subject>Oral administration</subject><subject>Penicillin</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Pteridines - 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Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26784926</pmid><doi>10.1371/journal.pone.0146835</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine triphosphatase AKT protein Amino Acid Sequence Binding Sites Biology Cell activation Cells, Cultured Chronic infection Dendritic cells Deoxyribonucleic acid Determinants DNA Drug resistance Drug therapy Genetic aspects HEK293 Cells Hepatitis Hepatitis B HIV infections Humans Immune system Immunoglobulins Immunology Ligands Molecular interactions Molecular Sequence Data Molecular structure Mutation NF-κB protein Oral administration Penicillin Physiological aspects Polymorphism, Single Nucleotide Protein Binding Proteins Pteridines - pharmacology Signal transduction Single-nucleotide polymorphism TLR7 protein Toll-Like Receptor 7 - agonists Toll-Like Receptor 7 - chemistry Toll-Like Receptor 7 - genetics Toll-Like Receptor 7 - metabolism Toll-like receptors |
| title | Molecular Determinants of GS-9620-Dependent TLR7 Activation |
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