A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction
Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue 1 , 2 . There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomo...
Gespeichert in:
| Veröffentlicht in: | Nature (London) 2021-10, Vol.598 (7881), p.504-509 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 509 |
|---|---|
| container_issue | 7881 |
| container_start_page | 504 |
| container_title | Nature (London) |
| container_volume | 598 |
| creator | Kaptein, Suzanne J. F. Goethals, Olivia Kiemel, Dominik Marchand, Arnaud Kesteleyn, Bart Bonfanti, Jean-François Bardiot, Dorothée Stoops, Bart Jonckers, Tim H. M. Dallmeier, Kai Geluykens, Peggy Thys, Kim Crabbe, Marjolein Chatel-Chaix, Laurent Münster, Max Querat, Gilles Touret, Franck de Lamballerie, Xavier Raboisson, Pierre Simmen, Kenny Chaltin, Patrick Bartenschlager, Ralf Van Loock, Marnix Neyts, Johan |
| description | Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue
1
,
2
. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.
The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia. |
| doi_str_mv | 10.1038/s41586-021-03990-6 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_04868312v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A679675666</galeid><sourcerecordid>A679675666</sourcerecordid><originalsourceid>FETCH-LOGICAL-c619t-c81a0e9b019312ef2f2c149f7263570259dcb89b82b0de9074365b087f8d06103</originalsourceid><addsrcrecordid>eNp9ks9u1DAQxiMEokvhBTigCE49uIxjx3-O24rSSqsisXC2nMTJutp1Utup6I136AvwLDwKT4KXlJaVVsgHSzO_-TTz6cuy1xiOMRDxPlBcCoagwAiIlIDYk2yGKWeIMsGfZjOAQiAQhB1kL0K4AoASc_o8OyCUYQaUzLLFPB-0Q8H4Pt4OJm-M60aT31g_hp8_rFvZysbe51H7zkTrujyuTH65JL--310u6cmWicbrOtrevcyetXodzKv7_zD7evbhy-k5Wnz6eHE6X6CaYRlRLbAGIyvAkuDCtEVb1JjKlheMlByKUjZ1JWQligoaI4FTwsoKBG9FAyydfpgdTborvVaDtxvtb1WvrTqfL9S2BlQwkbRvcGLfTezg--vRhKiu-tG7tJ4qSkF5WqGUj1Sn10ZZ1_Yx3bSxoVZzxiXjJWMsUWgP1RmXDFj3zrQ2lXf4t3v4erDX6l_oeA-UXmM2tt6rerQzkJhovsVOjyGoi-XnXbaY2Nr3IXjTPtiFQW1DpKYQqRQi9SdEajv05t6ysdqY5mHkb2oSQCYgpJbrjH_09D-yvwFc3M3z</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2584793159</pqid></control><display><type>article</type><title>A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Nature Journals Online</source><creator>Kaptein, Suzanne J. F. ; Goethals, Olivia ; Kiemel, Dominik ; Marchand, Arnaud ; Kesteleyn, Bart ; Bonfanti, Jean-François ; Bardiot, Dorothée ; Stoops, Bart ; Jonckers, Tim H. M. ; Dallmeier, Kai ; Geluykens, Peggy ; Thys, Kim ; Crabbe, Marjolein ; Chatel-Chaix, Laurent ; Münster, Max ; Querat, Gilles ; Touret, Franck ; de Lamballerie, Xavier ; Raboisson, Pierre ; Simmen, Kenny ; Chaltin, Patrick ; Bartenschlager, Ralf ; Van Loock, Marnix ; Neyts, Johan</creator><creatorcontrib>Kaptein, Suzanne J. F. ; Goethals, Olivia ; Kiemel, Dominik ; Marchand, Arnaud ; Kesteleyn, Bart ; Bonfanti, Jean-François ; Bardiot, Dorothée ; Stoops, Bart ; Jonckers, Tim H. M. ; Dallmeier, Kai ; Geluykens, Peggy ; Thys, Kim ; Crabbe, Marjolein ; Chatel-Chaix, Laurent ; Münster, Max ; Querat, Gilles ; Touret, Franck ; de Lamballerie, Xavier ; Raboisson, Pierre ; Simmen, Kenny ; Chaltin, Patrick ; Bartenschlager, Ralf ; Van Loock, Marnix ; Neyts, Johan</creatorcontrib><description>Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue
1
,
2
. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.
The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03990-6</identifier><identifier>PMID: 34616043</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 38/109 ; 38/47 ; 38/70 ; 38/90 ; 631/154/555 ; 631/326/596/1413 ; 64/110 ; 82/80 ; Animal models ; Animals ; Antiviral activity ; Antiviral agents ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Clinical isolates ; Dengue ; Dengue - drug therapy ; Dengue - virology ; Dengue fever ; Dengue Virus - classification ; Dengue Virus - drug effects ; Dengue Virus - genetics ; Dengue Virus - metabolism ; Dengue viruses ; Development and progression ; Disease Models, Animal ; Drug resistance ; Drug therapy ; Female ; Fever ; Genetic diversity ; Genotypes ; Health aspects ; Humanities and Social Sciences ; Inhibitors ; Life Sciences ; Male ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - metabolism ; Mice ; multidisciplinary ; Mutation ; Pharmacokinetics ; Physiological aspects ; Protein-protein interactions ; RNA Helicases - antagonists & inhibitors ; RNA Helicases - metabolism ; Science ; Science (multidisciplinary) ; Serine Endopeptidases - metabolism ; Serotypes ; Vector-borne diseases ; Viral diseases ; Viral Load - drug effects ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism ; Viral proteins ; Viremia ; Viremia - drug therapy ; Viremia - virology ; Virus Replication - drug effects ; Viruses</subject><ispartof>Nature (London), 2021-10, Vol.598 (7881), p.504-509</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021. corrected publication 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 21, 2021</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c619t-c81a0e9b019312ef2f2c149f7263570259dcb89b82b0de9074365b087f8d06103</citedby><cites>FETCH-LOGICAL-c619t-c81a0e9b019312ef2f2c149f7263570259dcb89b82b0de9074365b087f8d06103</cites><orcidid>0000-0002-8117-9166 ; 0000-0002-7390-8250 ; 0000-0001-5601-9307 ; 0000-0002-7935-0219 ; 0000-0002-0033-7514 ; 0000-0003-4151-4588 ; 0000-0002-2107-8857 ; 0000-0002-4734-2249</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03990-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03990-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34616043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04868312$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaptein, Suzanne J. F.</creatorcontrib><creatorcontrib>Goethals, Olivia</creatorcontrib><creatorcontrib>Kiemel, Dominik</creatorcontrib><creatorcontrib>Marchand, Arnaud</creatorcontrib><creatorcontrib>Kesteleyn, Bart</creatorcontrib><creatorcontrib>Bonfanti, Jean-François</creatorcontrib><creatorcontrib>Bardiot, Dorothée</creatorcontrib><creatorcontrib>Stoops, Bart</creatorcontrib><creatorcontrib>Jonckers, Tim H. M.</creatorcontrib><creatorcontrib>Dallmeier, Kai</creatorcontrib><creatorcontrib>Geluykens, Peggy</creatorcontrib><creatorcontrib>Thys, Kim</creatorcontrib><creatorcontrib>Crabbe, Marjolein</creatorcontrib><creatorcontrib>Chatel-Chaix, Laurent</creatorcontrib><creatorcontrib>Münster, Max</creatorcontrib><creatorcontrib>Querat, Gilles</creatorcontrib><creatorcontrib>Touret, Franck</creatorcontrib><creatorcontrib>de Lamballerie, Xavier</creatorcontrib><creatorcontrib>Raboisson, Pierre</creatorcontrib><creatorcontrib>Simmen, Kenny</creatorcontrib><creatorcontrib>Chaltin, Patrick</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Van Loock, Marnix</creatorcontrib><creatorcontrib>Neyts, Johan</creatorcontrib><title>A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue
1
,
2
. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.
The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia.</description><subject>13/1</subject><subject>13/106</subject><subject>38/109</subject><subject>38/47</subject><subject>38/70</subject><subject>38/90</subject><subject>631/154/555</subject><subject>631/326/596/1413</subject><subject>64/110</subject><subject>82/80</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antiviral activity</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Clinical isolates</subject><subject>Dengue</subject><subject>Dengue - drug therapy</subject><subject>Dengue - virology</subject><subject>Dengue fever</subject><subject>Dengue Virus - classification</subject><subject>Dengue Virus - drug effects</subject><subject>Dengue Virus - genetics</subject><subject>Dengue Virus - metabolism</subject><subject>Dengue viruses</subject><subject>Development and progression</subject><subject>Disease Models, Animal</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Fever</subject><subject>Genetic diversity</subject><subject>Genotypes</subject><subject>Health aspects</subject><subject>Humanities and Social Sciences</subject><subject>Inhibitors</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Pharmacokinetics</subject><subject>Physiological aspects</subject><subject>Protein-protein interactions</subject><subject>RNA Helicases - antagonists & inhibitors</subject><subject>RNA Helicases - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Serine Endopeptidases - metabolism</subject><subject>Serotypes</subject><subject>Vector-borne diseases</subject><subject>Viral diseases</subject><subject>Viral Load - drug effects</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Viral proteins</subject><subject>Viremia</subject><subject>Viremia - drug therapy</subject><subject>Viremia - virology</subject><subject>Virus Replication - drug effects</subject><subject>Viruses</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9ks9u1DAQxiMEokvhBTigCE49uIxjx3-O24rSSqsisXC2nMTJutp1Utup6I136AvwLDwKT4KXlJaVVsgHSzO_-TTz6cuy1xiOMRDxPlBcCoagwAiIlIDYk2yGKWeIMsGfZjOAQiAQhB1kL0K4AoASc_o8OyCUYQaUzLLFPB-0Q8H4Pt4OJm-M60aT31g_hp8_rFvZysbe51H7zkTrujyuTH65JL--310u6cmWicbrOtrevcyetXodzKv7_zD7evbhy-k5Wnz6eHE6X6CaYRlRLbAGIyvAkuDCtEVb1JjKlheMlByKUjZ1JWQligoaI4FTwsoKBG9FAyydfpgdTborvVaDtxvtb1WvrTqfL9S2BlQwkbRvcGLfTezg--vRhKiu-tG7tJ4qSkF5WqGUj1Sn10ZZ1_Yx3bSxoVZzxiXjJWMsUWgP1RmXDFj3zrQ2lXf4t3v4erDX6l_oeA-UXmM2tt6rerQzkJhovsVOjyGoi-XnXbaY2Nr3IXjTPtiFQW1DpKYQqRQi9SdEajv05t6ysdqY5mHkb2oSQCYgpJbrjH_09D-yvwFc3M3z</recordid><startdate>20211021</startdate><enddate>20211021</enddate><creator>Kaptein, Suzanne J. F.</creator><creator>Goethals, Olivia</creator><creator>Kiemel, Dominik</creator><creator>Marchand, Arnaud</creator><creator>Kesteleyn, Bart</creator><creator>Bonfanti, Jean-François</creator><creator>Bardiot, Dorothée</creator><creator>Stoops, Bart</creator><creator>Jonckers, Tim H. M.</creator><creator>Dallmeier, Kai</creator><creator>Geluykens, Peggy</creator><creator>Thys, Kim</creator><creator>Crabbe, Marjolein</creator><creator>Chatel-Chaix, Laurent</creator><creator>Münster, Max</creator><creator>Querat, Gilles</creator><creator>Touret, Franck</creator><creator>de Lamballerie, Xavier</creator><creator>Raboisson, Pierre</creator><creator>Simmen, Kenny</creator><creator>Chaltin, Patrick</creator><creator>Bartenschlager, Ralf</creator><creator>Van Loock, Marnix</creator><creator>Neyts, Johan</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-8117-9166</orcidid><orcidid>https://orcid.org/0000-0002-7390-8250</orcidid><orcidid>https://orcid.org/0000-0001-5601-9307</orcidid><orcidid>https://orcid.org/0000-0002-7935-0219</orcidid><orcidid>https://orcid.org/0000-0002-0033-7514</orcidid><orcidid>https://orcid.org/0000-0003-4151-4588</orcidid><orcidid>https://orcid.org/0000-0002-2107-8857</orcidid><orcidid>https://orcid.org/0000-0002-4734-2249</orcidid></search><sort><creationdate>20211021</creationdate><title>A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction</title><author>Kaptein, Suzanne J. F. ; Goethals, Olivia ; Kiemel, Dominik ; Marchand, Arnaud ; Kesteleyn, Bart ; Bonfanti, Jean-François ; Bardiot, Dorothée ; Stoops, Bart ; Jonckers, Tim H. M. ; Dallmeier, Kai ; Geluykens, Peggy ; Thys, Kim ; Crabbe, Marjolein ; Chatel-Chaix, Laurent ; Münster, Max ; Querat, Gilles ; Touret, Franck ; de Lamballerie, Xavier ; Raboisson, Pierre ; Simmen, Kenny ; Chaltin, Patrick ; Bartenschlager, Ralf ; Van Loock, Marnix ; Neyts, Johan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c619t-c81a0e9b019312ef2f2c149f7263570259dcb89b82b0de9074365b087f8d06103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/1</topic><topic>13/106</topic><topic>38/109</topic><topic>38/47</topic><topic>38/70</topic><topic>38/90</topic><topic>631/154/555</topic><topic>631/326/596/1413</topic><topic>64/110</topic><topic>82/80</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antiviral activity</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Clinical isolates</topic><topic>Dengue</topic><topic>Dengue - drug therapy</topic><topic>Dengue - virology</topic><topic>Dengue fever</topic><topic>Dengue Virus - classification</topic><topic>Dengue Virus - drug effects</topic><topic>Dengue Virus - genetics</topic><topic>Dengue Virus - metabolism</topic><topic>Dengue viruses</topic><topic>Development and progression</topic><topic>Disease Models, Animal</topic><topic>Drug resistance</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Fever</topic><topic>Genetic diversity</topic><topic>Genotypes</topic><topic>Health aspects</topic><topic>Humanities and Social Sciences</topic><topic>Inhibitors</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Pharmacokinetics</topic><topic>Physiological aspects</topic><topic>Protein-protein interactions</topic><topic>RNA Helicases - antagonists & inhibitors</topic><topic>RNA Helicases - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Serine Endopeptidases - metabolism</topic><topic>Serotypes</topic><topic>Vector-borne diseases</topic><topic>Viral diseases</topic><topic>Viral Load - drug effects</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>Viral proteins</topic><topic>Viremia</topic><topic>Viremia - drug therapy</topic><topic>Viremia - virology</topic><topic>Virus Replication - drug effects</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaptein, Suzanne J. F.</creatorcontrib><creatorcontrib>Goethals, Olivia</creatorcontrib><creatorcontrib>Kiemel, Dominik</creatorcontrib><creatorcontrib>Marchand, Arnaud</creatorcontrib><creatorcontrib>Kesteleyn, Bart</creatorcontrib><creatorcontrib>Bonfanti, Jean-François</creatorcontrib><creatorcontrib>Bardiot, Dorothée</creatorcontrib><creatorcontrib>Stoops, Bart</creatorcontrib><creatorcontrib>Jonckers, Tim H. M.</creatorcontrib><creatorcontrib>Dallmeier, Kai</creatorcontrib><creatorcontrib>Geluykens, Peggy</creatorcontrib><creatorcontrib>Thys, Kim</creatorcontrib><creatorcontrib>Crabbe, Marjolein</creatorcontrib><creatorcontrib>Chatel-Chaix, Laurent</creatorcontrib><creatorcontrib>Münster, Max</creatorcontrib><creatorcontrib>Querat, Gilles</creatorcontrib><creatorcontrib>Touret, Franck</creatorcontrib><creatorcontrib>de Lamballerie, Xavier</creatorcontrib><creatorcontrib>Raboisson, Pierre</creatorcontrib><creatorcontrib>Simmen, Kenny</creatorcontrib><creatorcontrib>Chaltin, Patrick</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Van Loock, Marnix</creatorcontrib><creatorcontrib>Neyts, Johan</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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Earth, Atmospheric & Aquatic Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</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 One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaptein, Suzanne J. F.</au><au>Goethals, Olivia</au><au>Kiemel, Dominik</au><au>Marchand, Arnaud</au><au>Kesteleyn, Bart</au><au>Bonfanti, Jean-François</au><au>Bardiot, Dorothée</au><au>Stoops, Bart</au><au>Jonckers, Tim H. M.</au><au>Dallmeier, Kai</au><au>Geluykens, Peggy</au><au>Thys, Kim</au><au>Crabbe, Marjolein</au><au>Chatel-Chaix, Laurent</au><au>Münster, Max</au><au>Querat, Gilles</au><au>Touret, Franck</au><au>de Lamballerie, Xavier</au><au>Raboisson, Pierre</au><au>Simmen, Kenny</au><au>Chaltin, Patrick</au><au>Bartenschlager, Ralf</au><au>Van Loock, Marnix</au><au>Neyts, Johan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-10-21</date><risdate>2021</risdate><volume>598</volume><issue>7881</issue><spage>504</spage><epage>509</epage><pages>504-509</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue
1
,
2
. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.
The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34616043</pmid><doi>10.1038/s41586-021-03990-6</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-8117-9166</orcidid><orcidid>https://orcid.org/0000-0002-7390-8250</orcidid><orcidid>https://orcid.org/0000-0001-5601-9307</orcidid><orcidid>https://orcid.org/0000-0002-7935-0219</orcidid><orcidid>https://orcid.org/0000-0002-0033-7514</orcidid><orcidid>https://orcid.org/0000-0003-4151-4588</orcidid><orcidid>https://orcid.org/0000-0002-2107-8857</orcidid><orcidid>https://orcid.org/0000-0002-4734-2249</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-10, Vol.598 (7881), p.504-509 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_04868312v1 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 13/1 13/106 38/109 38/47 38/70 38/90 631/154/555 631/326/596/1413 64/110 82/80 Animal models Animals Antiviral activity Antiviral agents Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Clinical isolates Dengue Dengue - drug therapy Dengue - virology Dengue fever Dengue Virus - classification Dengue Virus - drug effects Dengue Virus - genetics Dengue Virus - metabolism Dengue viruses Development and progression Disease Models, Animal Drug resistance Drug therapy Female Fever Genetic diversity Genotypes Health aspects Humanities and Social Sciences Inhibitors Life Sciences Male Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Mice multidisciplinary Mutation Pharmacokinetics Physiological aspects Protein-protein interactions RNA Helicases - antagonists & inhibitors RNA Helicases - metabolism Science Science (multidisciplinary) Serine Endopeptidases - metabolism Serotypes Vector-borne diseases Viral diseases Viral Load - drug effects Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Viral proteins Viremia Viremia - drug therapy Viremia - virology Virus Replication - drug effects Viruses |
| title | A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T05%3A43%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20pan-serotype%20dengue%20virus%C2%A0inhibitor%20targeting%20the%20NS3%E2%80%93NS4B%C2%A0interaction&rft.jtitle=Nature%20(London)&rft.au=Kaptein,%20Suzanne%20J.%20F.&rft.date=2021-10-21&rft.volume=598&rft.issue=7881&rft.spage=504&rft.epage=509&rft.pages=504-509&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03990-6&rft_dat=%3Cgale_hal_p%3EA679675666%3C/gale_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2584793159&rft_id=info:pmid/34616043&rft_galeid=A679675666&rfr_iscdi=true |