Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles
Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious...
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| Veröffentlicht in: | Nature reviews. Drug discovery 2019-11, Vol.18 (11), p.845-867 |
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| creator | Vanpouille-Box, Claire Hoffmann, Jules A. Galluzzi, Lorenzo |
| description | Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.
Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development. |
| doi_str_mv | 10.1038/s41573-019-0043-2 |
| format | Article |
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Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.</description><identifier>ISSN: 1474-1776</identifier><identifier>EISSN: 1474-1784</identifier><identifier>DOI: 10.1038/s41573-019-0043-2</identifier><identifier>PMID: 31554927</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154 ; 631/250/249/1313 ; 631/250/255 ; 631/67 ; 631/92/610 ; 692/698/1543/1565 ; Acids ; Animals ; Antineoplastic Agents - therapeutic use ; Autophagy ; Biomedical and Life Sciences ; Biomedicine ; Biotechnology ; Breast cancer ; Cancer Research ; Cancer therapies ; Cancer Vaccines - therapeutic use ; Control ; Deoxyribonucleic acid ; DNA ; Health aspects ; Homeostasis ; Humans ; Immunity, Innate - immunology ; Immunotherapy ; Infectious diseases ; Insects ; Lupus ; Medical research ; Medicinal Chemistry ; Mitochondrial DNA ; Molecular Medicine ; Neoplasms - immunology ; Neoplasms - prevention & control ; Nucleic acids ; Nucleic Acids - immunology ; Pharmacology/Toxicology ; Review Article ; RNA polymerase ; Sensors ; Signal Transduction ; Tuberculosis</subject><ispartof>Nature reviews. Drug discovery, 2019-11, Vol.18 (11), p.845-867</ispartof><rights>Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 2019</rights><rights>Springer Nature Limited 2019.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-32bb38b77f3e5764da3c70a1f919c519443be80d1f3ea847f8190e5f0a1c893</citedby><cites>FETCH-LOGICAL-c533t-32bb38b77f3e5764da3c70a1f919c519443be80d1f3ea847f8190e5f0a1c893</cites><orcidid>0000-0001-7213-0670 ; 0000-0003-2257-8500</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31554927$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vanpouille-Box, Claire</creatorcontrib><creatorcontrib>Hoffmann, Jules A.</creatorcontrib><creatorcontrib>Galluzzi, Lorenzo</creatorcontrib><title>Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles</title><title>Nature reviews. Drug discovery</title><addtitle>Nat Rev Drug Discov</addtitle><addtitle>Nat Rev Drug Discov</addtitle><description>Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.
Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.</description><subject>631/154</subject><subject>631/250/249/1313</subject><subject>631/250/255</subject><subject>631/67</subject><subject>631/92/610</subject><subject>692/698/1543/1565</subject><subject>Acids</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Autophagy</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Breast cancer</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Cancer Vaccines - therapeutic use</subject><subject>Control</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Health aspects</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunity, Innate - immunology</subject><subject>Immunotherapy</subject><subject>Infectious diseases</subject><subject>Insects</subject><subject>Lupus</subject><subject>Medical research</subject><subject>Medicinal Chemistry</subject><subject>Mitochondrial DNA</subject><subject>Molecular Medicine</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - prevention & control</subject><subject>Nucleic acids</subject><subject>Nucleic Acids - immunology</subject><subject>Pharmacology/Toxicology</subject><subject>Review Article</subject><subject>RNA polymerase</subject><subject>Sensors</subject><subject>Signal Transduction</subject><subject>Tuberculosis</subject><issn>1474-1776</issn><issn>1474-1784</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kc1u1TAQhS0EouXCA7BBkdiwSfH4J46XVcWfVAkk2FuOM7l1ldjBdhbs-hA8IU-Cr25pBQLkhS3Pd86MfQh5DvQMKO9fZwFS8ZaCbikVvGUPyCkIJVpQvXh4d1bdCXmS8zWl0IFij8kJBymFZuqU4Kcrmxbr4hz33tm5WeK4zbb4GJo4NWFzM3rXWOfHJmPIMeXmx833plxhsitupRbXWDAUX8U2jM2KKftcfNg3ccjFVoP8lDya7Jzx2e2-I5_fvvly8b69_Pjuw8X5Zesk56XlbBh4Pyg1cZSqE6PlTlELkwbtJGgh-IA9HaHWbS_U1IOmKKeKuF7zHXl1dF1T_LphLmbx2eE824Bxy4Yx3YOQ9esq-vIP9DpuKdTZDOu05IwJ_X-KA9VadrS7p_Z2RuPDFEuy7tDanHdUiA46KSt19heqrhEX72LAydf73wRwFLgUc044mTX5xaZvBqg5xG-O8ZsavznEX2fakRe3A2_DguOd4lfeFWBHINdS2GO6f9G_XX8C8ky5bg</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Vanpouille-Box, Claire</creator><creator>Hoffmann, Jules A.</creator><creator>Galluzzi, Lorenzo</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7213-0670</orcidid><orcidid>https://orcid.org/0000-0003-2257-8500</orcidid></search><sort><creationdate>20191101</creationdate><title>Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles</title><author>Vanpouille-Box, Claire ; Hoffmann, Jules A. ; Galluzzi, Lorenzo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c533t-32bb38b77f3e5764da3c70a1f919c519443be80d1f3ea847f8190e5f0a1c893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>631/154</topic><topic>631/250/249/1313</topic><topic>631/250/255</topic><topic>631/67</topic><topic>631/92/610</topic><topic>692/698/1543/1565</topic><topic>Acids</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Autophagy</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>Breast cancer</topic><topic>Cancer Research</topic><topic>Cancer therapies</topic><topic>Cancer Vaccines - therapeutic use</topic><topic>Control</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Health aspects</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunity, Innate - immunology</topic><topic>Immunotherapy</topic><topic>Infectious diseases</topic><topic>Insects</topic><topic>Lupus</topic><topic>Medical research</topic><topic>Medicinal Chemistry</topic><topic>Mitochondrial DNA</topic><topic>Molecular Medicine</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - prevention & control</topic><topic>Nucleic acids</topic><topic>Nucleic Acids - immunology</topic><topic>Pharmacology/Toxicology</topic><topic>Review Article</topic><topic>RNA polymerase</topic><topic>Sensors</topic><topic>Signal Transduction</topic><topic>Tuberculosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vanpouille-Box, Claire</creatorcontrib><creatorcontrib>Hoffmann, Jules A.</creatorcontrib><creatorcontrib>Galluzzi, Lorenzo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Nature reviews. Drug discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vanpouille-Box, Claire</au><au>Hoffmann, Jules A.</au><au>Galluzzi, Lorenzo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles</atitle><jtitle>Nature reviews. Drug discovery</jtitle><stitle>Nat Rev Drug Discov</stitle><addtitle>Nat Rev Drug Discov</addtitle><date>2019-11-01</date><risdate>2019</risdate><volume>18</volume><issue>11</issue><spage>845</spage><epage>867</epage><pages>845-867</pages><issn>1474-1776</issn><eissn>1474-1784</eissn><abstract>Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS–STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.
Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31554927</pmid><doi>10.1038/s41573-019-0043-2</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0001-7213-0670</orcidid><orcidid>https://orcid.org/0000-0003-2257-8500</orcidid></addata></record> |
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| subjects | 631/154 631/250/249/1313 631/250/255 631/67 631/92/610 692/698/1543/1565 Acids Animals Antineoplastic Agents - therapeutic use Autophagy Biomedical and Life Sciences Biomedicine Biotechnology Breast cancer Cancer Research Cancer therapies Cancer Vaccines - therapeutic use Control Deoxyribonucleic acid DNA Health aspects Homeostasis Humans Immunity, Innate - immunology Immunotherapy Infectious diseases Insects Lupus Medical research Medicinal Chemistry Mitochondrial DNA Molecular Medicine Neoplasms - immunology Neoplasms - prevention & control Nucleic acids Nucleic Acids - immunology Pharmacology/Toxicology Review Article RNA polymerase Sensors Signal Transduction Tuberculosis |
| title | Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles |
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