The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway
The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. He...
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| Veröffentlicht in: | Microbial cell factories 2014-01, Vol.13 (1), p.17-17, Article 17 |
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| creator | Fleta-Soriano, Eric Martinez, Javier P Hinkelmann, Bettina Gerth, Klaus Washausen, Peter Diez, Juana Frank, Ronald Sasse, Florenz Meyerhans, Andreas |
| description | The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria.
Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC₅₀ values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev.
Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future. |
| doi_str_mv | 10.1186/1475-2859-13-17 |
| format | Article |
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Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC₅₀ values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev.
Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future.</description><identifier>ISSN: 1475-2859</identifier><identifier>EISSN: 1475-2859</identifier><identifier>DOI: 10.1186/1475-2859-13-17</identifier><identifier>PMID: 24475978</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Active Transport, Cell Nucleus - drug effects ; Antiviral Agents - pharmacology ; Cell Line ; CRM1 ; Cytoplasm ; Drug dosages ; Drug therapy ; Exportin 1 Protein ; Exports ; Gene expression ; Health aspects ; Health sciences ; HIV ; HIV Core Protein p24 - metabolism ; HIV infection ; HIV Infections - prevention & control ; HIV-1 - metabolism ; Host factor ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Immunodeficiència ; Infections ; Karyopherins - antagonists & inhibitors ; Karyopherins - metabolism ; Metabolites ; Myxobacteria ; Myxococcales - metabolism ; Nuclear export ; Protein Binding ; Proteins ; Pyrones - chemistry ; Pyrones - metabolism ; Pyrones - pharmacology ; Ratjadone ; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors ; Receptors, Cytoplasmic and Nuclear - metabolism ; Rev ; rev Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors ; rev Gene Products, Human Immunodeficiency Virus - metabolism ; RNA missatger ; RNA, Messenger - metabolism ; VIH (Virus)</subject><ispartof>Microbial cell factories, 2014-01, Vol.13 (1), p.17-17, Article 17</ispartof><rights>COPYRIGHT 2014 BioMed Central Ltd.</rights><rights>2014 Fleta-Soriano et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>info:eu-repo/semantics/openAccess © 2014 Fleta-Soriano et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (<a href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</a>) applies to the data made available in this article, unless otherwise stated. <a href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</a></rights><rights>Copyright © 2014 Fleta-Soriano et al.; licensee BioMed Central Ltd. 2014 Fleta-Soriano et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c597t-b0b0dfdaeae4d9a3eb2b16719866bf6f801dc4c67aeab9938660289d614baf483</citedby><cites>FETCH-LOGICAL-c597t-b0b0dfdaeae4d9a3eb2b16719866bf6f801dc4c67aeab9938660289d614baf483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910686/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910686/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,26953,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24475978$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fleta-Soriano, Eric</creatorcontrib><creatorcontrib>Martinez, Javier P</creatorcontrib><creatorcontrib>Hinkelmann, Bettina</creatorcontrib><creatorcontrib>Gerth, Klaus</creatorcontrib><creatorcontrib>Washausen, Peter</creatorcontrib><creatorcontrib>Diez, Juana</creatorcontrib><creatorcontrib>Frank, Ronald</creatorcontrib><creatorcontrib>Sasse, Florenz</creatorcontrib><creatorcontrib>Meyerhans, Andreas</creatorcontrib><title>The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway</title><title>Microbial cell factories</title><addtitle>Microb Cell Fact</addtitle><description>The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria.
Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC₅₀ values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev.
Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future.</description><subject>Active Transport, Cell Nucleus - drug effects</subject><subject>Antiviral Agents - pharmacology</subject><subject>Cell Line</subject><subject>CRM1</subject><subject>Cytoplasm</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Exportin 1 Protein</subject><subject>Exports</subject><subject>Gene expression</subject><subject>Health aspects</subject><subject>Health sciences</subject><subject>HIV</subject><subject>HIV Core Protein p24 - metabolism</subject><subject>HIV infection</subject><subject>HIV Infections - prevention & control</subject><subject>HIV-1 - metabolism</subject><subject>Host factor</subject><subject>Human immunodeficiency virus</subject><subject>Human immunodeficiency virus 1</subject><subject>Humans</subject><subject>Immunodeficiència</subject><subject>Infections</subject><subject>Karyopherins - antagonists & inhibitors</subject><subject>Karyopherins - metabolism</subject><subject>Metabolites</subject><subject>Myxobacteria</subject><subject>Myxococcales - metabolism</subject><subject>Nuclear export</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Pyrones - chemistry</subject><subject>Pyrones - metabolism</subject><subject>Pyrones - pharmacology</subject><subject>Ratjadone</subject><subject>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Rev</subject><subject>rev Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors</subject><subject>rev Gene Products, Human Immunodeficiency Virus - metabolism</subject><subject>RNA missatger</subject><subject>RNA, Messenger - metabolism</subject><subject>VIH (Virus)</subject><issn>1475-2859</issn><issn>1475-2859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>XX2</sourceid><recordid>eNptktFv0zAQxiMEYmPwzBuyxAs8ZLXjxI5fkKoKWKUhpDF4tWzn0rokcbGd0f73OKyUFSErsu_8uy-XL5dlLwm-JKRmM1LyKi_qSuSE5oQ_ys6PmccPzmfZsxA2GBNec_o0OyvKdCN4fZ7tbteA-v3OaWUieKs61ENU2nU2AvIqblTjBkBzZIe11TYGdLX8loIWTLRuQHqPdOfMdzusUExaN3A3W9x8InkPjVURGjSMpgPlEey2zke0VXH9U-2fZ09a1QV4cdgvsq8f3t8urvLrzx-Xi_l1blKDMddY46ZtFCgoG6Eo6EITxomoGdMta2tMGlMaxhOhhaApjYtaNIyUWrVlTS-yd_e621GnlgwM0atObr3tld9Lp6w8vRnsWq7cnaSCYFazJEDuBUwYjfRgwBsVfxceg-kpMC8kJVVRkFTz5vBS736MEKLsbTDQdWoANwZJKow5FwzzhL7-B9240Q_JEklKURJKK0H-UivVgUzuu9SrmUTlvKKCFayucaIu_0Ol1UBvTfqNrU35k4K3JwWJibCLKzWGIJdfbk7Z2cEH70Lw0B49JFhOwyincZPTuElCJZk-7dVD64_8n-mjvwDeXtlr</recordid><startdate>20140129</startdate><enddate>20140129</enddate><creator>Fleta-Soriano, Eric</creator><creator>Martinez, Javier P</creator><creator>Hinkelmann, Bettina</creator><creator>Gerth, Klaus</creator><creator>Washausen, Peter</creator><creator>Diez, Juana</creator><creator>Frank, Ronald</creator><creator>Sasse, Florenz</creator><creator>Meyerhans, Andreas</creator><general>BioMed Central Ltd</general><general>BioMed Central</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>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>7U7</scope><scope>XX2</scope><scope>5PM</scope></search><sort><creationdate>20140129</creationdate><title>The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway</title><author>Fleta-Soriano, Eric ; Martinez, Javier P ; Hinkelmann, Bettina ; Gerth, Klaus ; Washausen, Peter ; Diez, Juana ; Frank, Ronald ; Sasse, Florenz ; Meyerhans, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c597t-b0b0dfdaeae4d9a3eb2b16719866bf6f801dc4c67aeab9938660289d614baf483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Active Transport, Cell Nucleus - drug effects</topic><topic>Antiviral Agents - pharmacology</topic><topic>Cell Line</topic><topic>CRM1</topic><topic>Cytoplasm</topic><topic>Drug dosages</topic><topic>Drug therapy</topic><topic>Exportin 1 Protein</topic><topic>Exports</topic><topic>Gene expression</topic><topic>Health aspects</topic><topic>Health sciences</topic><topic>HIV</topic><topic>HIV Core Protein p24 - metabolism</topic><topic>HIV infection</topic><topic>HIV Infections - prevention & control</topic><topic>HIV-1 - metabolism</topic><topic>Host factor</topic><topic>Human immunodeficiency virus</topic><topic>Human immunodeficiency virus 1</topic><topic>Humans</topic><topic>Immunodeficiència</topic><topic>Infections</topic><topic>Karyopherins - antagonists & inhibitors</topic><topic>Karyopherins - metabolism</topic><topic>Metabolites</topic><topic>Myxobacteria</topic><topic>Myxococcales - metabolism</topic><topic>Nuclear export</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Pyrones - chemistry</topic><topic>Pyrones - 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This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria.
Ratjadone A inhibits HIV infection in vitro in a dose-dependent manner with EC₅₀ values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev.
Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>24475978</pmid><doi>10.1186/1475-2859-13-17</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Active Transport, Cell Nucleus - drug effects Antiviral Agents - pharmacology Cell Line CRM1 Cytoplasm Drug dosages Drug therapy Exportin 1 Protein Exports Gene expression Health aspects Health sciences HIV HIV Core Protein p24 - metabolism HIV infection HIV Infections - prevention & control HIV-1 - metabolism Host factor Human immunodeficiency virus Human immunodeficiency virus 1 Humans Immunodeficiència Infections Karyopherins - antagonists & inhibitors Karyopherins - metabolism Metabolites Myxobacteria Myxococcales - metabolism Nuclear export Protein Binding Proteins Pyrones - chemistry Pyrones - metabolism Pyrones - pharmacology Ratjadone Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Receptors, Cytoplasmic and Nuclear - metabolism Rev rev Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors rev Gene Products, Human Immunodeficiency Virus - metabolism RNA missatger RNA, Messenger - metabolism VIH (Virus) |
| title | The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway |
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