The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5- d ]pyrimidin-7(6 H )-ones) with potent in vitro...
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| Veröffentlicht in: | Scientific reports 2016-08, Vol.6 (1), p.31819-31819, Article 31819 |
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| creator | Delang, L. Li, C. Tas, A. Quérat, G. Albulescu, I. C. De Burghgraeve, T. Guerrero, N. A. Segura Gigante, A. Piorkowski, G. Decroly, E. Jochmans, D. Canard, B. Snijder, E. J. Pérez-Pérez, M. J. van Hemert, M. J. Coutard, B. Leyssen, P. Neyts, J. |
| description | The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-
d
]pyrimidin-7(6
H
)-ones) with potent
in vitro
activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections. |
| doi_str_mv | 10.1038/srep31819 |
| format | Article |
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d
]pyrimidin-7(6
H
)-ones) with potent
in vitro
activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep31819</identifier><identifier>PMID: 27545976</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 13/109 ; 38/23 ; 42/70 ; 49/47 ; 49/90 ; 631/326/596/1282 ; 631/326/596/1296 ; 82/29 ; 82/83 ; Biochemistry, Molecular Biology ; Humanities and Social Sciences ; Life Sciences ; Microbiology and Parasitology ; multidisciplinary ; Pharmaceutical sciences ; Pharmacology ; Quantitative Methods ; Science ; Science (multidisciplinary) ; Structural Biology ; Virology</subject><ispartof>Scientific reports, 2016-08, Vol.6 (1), p.31819-31819, Article 31819</ispartof><rights>The Author(s) 2016</rights><rights>Attribution</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c444t-cb3600b1b40d9db5cf594582ea5e3c6c6e7ebb20ce156f8b603d072d825a64a23</citedby><cites>FETCH-LOGICAL-c444t-cb3600b1b40d9db5cf594582ea5e3c6c6e7ebb20ce156f8b603d072d825a64a23</cites><orcidid>0000-0002-6046-024X ; 0000-0003-4924-1991</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992889/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992889/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27545976$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-01439113$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Delang, L.</creatorcontrib><creatorcontrib>Li, C.</creatorcontrib><creatorcontrib>Tas, A.</creatorcontrib><creatorcontrib>Quérat, G.</creatorcontrib><creatorcontrib>Albulescu, I. C.</creatorcontrib><creatorcontrib>De Burghgraeve, T.</creatorcontrib><creatorcontrib>Guerrero, N. A. Segura</creatorcontrib><creatorcontrib>Gigante, A.</creatorcontrib><creatorcontrib>Piorkowski, G.</creatorcontrib><creatorcontrib>Decroly, E.</creatorcontrib><creatorcontrib>Jochmans, D.</creatorcontrib><creatorcontrib>Canard, B.</creatorcontrib><creatorcontrib>Snijder, E. J.</creatorcontrib><creatorcontrib>Pérez-Pérez, M. J.</creatorcontrib><creatorcontrib>van Hemert, M. J.</creatorcontrib><creatorcontrib>Coutard, B.</creatorcontrib><creatorcontrib>Leyssen, P.</creatorcontrib><creatorcontrib>Neyts, J.</creatorcontrib><title>The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-
d
]pyrimidin-7(6
H
)-ones) with potent
in vitro
activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.</description><subject>13</subject><subject>13/106</subject><subject>13/109</subject><subject>38/23</subject><subject>42/70</subject><subject>49/47</subject><subject>49/90</subject><subject>631/326/596/1282</subject><subject>631/326/596/1296</subject><subject>82/29</subject><subject>82/83</subject><subject>Biochemistry, Molecular Biology</subject><subject>Humanities and Social Sciences</subject><subject>Life Sciences</subject><subject>Microbiology and Parasitology</subject><subject>multidisciplinary</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Quantitative Methods</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Structural Biology</subject><subject>Virology</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><recordid>eNptkU-LFDEQxYMo7rLuwS8gOaowmv_T8SAsi7rCgB7Wc0jS1d1Ze5I26R4YP70ZZh1XMZcKea9-oeoh9JySN5Tw5m3JMHHaUP0InTMi5Ipxxh4_uJ-hy1LuSD2SaUH1U3TG1lJIvVbnyNwOgHch2xF7O00h9hjiz_0WcCxf6TtscUw7GPFscw8z7lLGc-0IcQguzCFFnDrsh_B9if0S9_bAWkrVO_AH-Rl60tmxwOV9vUDfPn64vb5Zbb58-nx9tVl5IcS88o4rQhx1grS6ddJ3UgvZMLASuFdewRqcY8QDlaprnCK8JWvWNkxaJSzjF-j9kTstbguthzjXmcyUw9bmvUk2mL-VGAbTp50RWrOm0RXw6ggY_mm7udqYwxuhgmtK-Y5W78v7z3L6sUCZzTYUD-NoI6SlmJoGV4xqov5gfU6lRtWd2JSYQ37mlF_1vng4w8n5O61qeH00lCrFHrK5S0uOda__of0C9pKlXQ</recordid><startdate>20160822</startdate><enddate>20160822</enddate><creator>Delang, L.</creator><creator>Li, C.</creator><creator>Tas, A.</creator><creator>Quérat, G.</creator><creator>Albulescu, I. 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J.</au><au>Coutard, B.</au><au>Leyssen, P.</au><au>Neyts, J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-08-22</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>31819</spage><epage>31819</epage><pages>31819-31819</pages><artnum>31819</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-
d
]pyrimidin-7(6
H
)-ones) with potent
in vitro
activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27545976</pmid><doi>10.1038/srep31819</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-6046-024X</orcidid><orcidid>https://orcid.org/0000-0003-4924-1991</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/106 13/109 38/23 42/70 49/47 49/90 631/326/596/1282 631/326/596/1296 82/29 82/83 Biochemistry, Molecular Biology Humanities and Social Sciences Life Sciences Microbiology and Parasitology multidisciplinary Pharmaceutical sciences Pharmacology Quantitative Methods Science Science (multidisciplinary) Structural Biology Virology |
| title | The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection |
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