A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase
[7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of in vitro bovine viral diarrhea virus (BVDV) replication. The EC 50 values for inhibition of BVDV-induced cytopathic effect (CPE) formation, vir...
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| Veröffentlicht in: | Antiviral research 2009-06, Vol.82 (3), p.141-147 |
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| creator | Paeshuyse, Jan Letellier, Carine Froeyen, Matheus Dutartre, Hélène Vrancken, Robert Canard, Bruno De Clercq, Erik Gueiffier, Alain Teulade, Jean-Claude Herdewijn, Piet Puerstinger, Gerhard Koenen, Frank Kerkhofs, Pierre Baraldi, Pier Giovanni Neyts, Johan |
| description | [7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of
in vitro bovine viral diarrhea virus (BVDV) replication. The EC
50 values for inhibition of BVDV-induced cytopathic effect (CPE) formation, viral RNA synthesis and production of infectious virus were 4.3
±
0.7
μM, 12.9
±
1
μM and 5.8
±
0.6
μM, respectively. LZ37 proved inactive against the hepatitis C virus and the flavivirus yellow fever. LZ37 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carried the F224Y mutation in the viral RNA-dependent RNA polymerase (RdRp). LZ37 showed cross-resistance with the imidazopyrrolopyridine AG110 [which selects for the E291G drug resistance mutation] as well as with the imidazopyridine BPIP [which selects for the F224S drug-resistant mutation]. LZ37 did not inhibit the
in vitro activity of purified recombinant BVDV RdRp. Molecular modelling revealed that F224 is located near the tip of the finger domain of the RdRp. Docking of LZ37 in the crystal structure of the BVDV RdRp revealed several potential contacts including: (i) hydrophobic contacts of LZ37 with A221, A222, G223, F224 and A392; (ii) a stacking interaction between F224 side chain and the ring system of LZ37 and (iii) a hydrogen bond between the amino function of LZ37 and the O backbone atom of A392. It is concluded that LZ37 interacts with the same binding site as BPIP or VP32947 at the top of the finger domain of the polymerase that is a “hot spot” for inhibition of pestivirus replication. |
| doi_str_mv | 10.1016/j.antiviral.2009.02.192 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_02459207v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0166354209002332</els_id><sourcerecordid>20521335</sourcerecordid><originalsourceid>FETCH-LOGICAL-c464t-2d827a907600d2218c3976e0aa450f20e922ca7ccabacade8c864ae54fc1b4633</originalsourceid><addsrcrecordid>eNqFkcGO0zAQhi0EYsvCK0AuIHFIsB3HiY_RClikCiQEZ2viTKirJA62W6m8AW-Nsy3lyGn0j75_xuOfkFeMFowy-W5fwBzt0XoYC06pKigvmOKPyIY1Nc8VVfIx2SRS5mUl-A15FsKeUipr1TwlN0wJ3khabcjvNltOHn650UVvH2rSdrK9nWGyM2Z23tnORuczN2SdO669h8VZb8H7HcIqDyHzuIzWQLRuzuIOYhbB_8AYkvjr-Pq5zXtccO5xjqvKFjeeJvQQ8Dl5MsAY8MWl3pLvH95_u7vPt18-frprt7kRUsSc9w2vQdFaUtpzzhpTqloiBRAVHThFxbmB2hjowECPjWmkAKzEYFgnZFnekrfnuTsY9ZJOBX_SDqy-b7d67VEuKsVpfWSJfXNmF-9-HjBEPdlgcBxhRncImtOKs7KsElifQeNdCB6H62RG9ZqY3utrYnpNLK3RKbHkfHlZcegm7P_5LhEl4PUFgGBgHDzMxoYrx5kouRDrXe2Zw_R5R4teB2NxNthbjybq3tn_PuYPS4m7zQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20521335</pqid></control><display><type>article</type><title>A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Paeshuyse, Jan ; Letellier, Carine ; Froeyen, Matheus ; Dutartre, Hélène ; Vrancken, Robert ; Canard, Bruno ; De Clercq, Erik ; Gueiffier, Alain ; Teulade, Jean-Claude ; Herdewijn, Piet ; Puerstinger, Gerhard ; Koenen, Frank ; Kerkhofs, Pierre ; Baraldi, Pier Giovanni ; Neyts, Johan</creator><creatorcontrib>Paeshuyse, Jan ; Letellier, Carine ; Froeyen, Matheus ; Dutartre, Hélène ; Vrancken, Robert ; Canard, Bruno ; De Clercq, Erik ; Gueiffier, Alain ; Teulade, Jean-Claude ; Herdewijn, Piet ; Puerstinger, Gerhard ; Koenen, Frank ; Kerkhofs, Pierre ; Baraldi, Pier Giovanni ; Neyts, Johan</creatorcontrib><description>[7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of
in vitro bovine viral diarrhea virus (BVDV) replication. The EC
50 values for inhibition of BVDV-induced cytopathic effect (CPE) formation, viral RNA synthesis and production of infectious virus were 4.3
±
0.7
μM, 12.9
±
1
μM and 5.8
±
0.6
μM, respectively. LZ37 proved inactive against the hepatitis C virus and the flavivirus yellow fever. LZ37 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carried the F224Y mutation in the viral RNA-dependent RNA polymerase (RdRp). LZ37 showed cross-resistance with the imidazopyrrolopyridine AG110 [which selects for the E291G drug resistance mutation] as well as with the imidazopyridine BPIP [which selects for the F224S drug-resistant mutation]. LZ37 did not inhibit the
in vitro activity of purified recombinant BVDV RdRp. Molecular modelling revealed that F224 is located near the tip of the finger domain of the RdRp. Docking of LZ37 in the crystal structure of the BVDV RdRp revealed several potential contacts including: (i) hydrophobic contacts of LZ37 with A221, A222, G223, F224 and A392; (ii) a stacking interaction between F224 side chain and the ring system of LZ37 and (iii) a hydrogen bond between the amino function of LZ37 and the O backbone atom of A392. It is concluded that LZ37 interacts with the same binding site as BPIP or VP32947 at the top of the finger domain of the polymerase that is a “hot spot” for inhibition of pestivirus replication.</description><identifier>ISSN: 0166-3542</identifier><identifier>EISSN: 1872-9096</identifier><identifier>DOI: 10.1016/j.antiviral.2009.02.192</identifier><identifier>PMID: 19428605</identifier><identifier>CODEN: ARSRDR</identifier><language>eng</language><publisher>Kidlington: Elsevier B.V</publisher><subject>Amino Acid Substitution - genetics ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Benzodioxoles - chemistry ; Benzodioxoles - pharmacology ; Biological and medical sciences ; Bovine viral diarrhea virus ; Cattle ; Cell Line ; Diarrhea Virus 1, Bovine Viral - drug effects ; Diarrhea Virus 1, Bovine Viral - physiology ; Diarrhea Virus 2, Bovine Viral - drug effects ; Diarrhea Virus 2, Bovine Viral - physiology ; Drug Resistance, Viral ; Flavivirus ; Hepacivirus - drug effects ; Hepatitis C virus ; Inhibitor ; Inhibitory Concentration 50 ; Life Sciences ; Medical sciences ; Microbiology and Parasitology ; Models, Molecular ; Mutation, Missense ; Pestivirus ; Pharmacology. Drug treatments ; Pyrazolotriazolopyrimidinamine ; RNA Replicase - chemistry ; RNA Replicase - genetics ; RNA-dependent RNA polymerase ; Triazoles - chemistry ; Triazoles - pharmacology ; Viral Proteins - genetics ; Virology ; Virus Replication - drug effects ; Yellow fever virus - drug effects</subject><ispartof>Antiviral research, 2009-06, Vol.82 (3), p.141-147</ispartof><rights>2009 Elsevier B.V.</rights><rights>2009 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-2d827a907600d2218c3976e0aa450f20e922ca7ccabacade8c864ae54fc1b4633</citedby><cites>FETCH-LOGICAL-c464t-2d827a907600d2218c3976e0aa450f20e922ca7ccabacade8c864ae54fc1b4633</cites><orcidid>0000-0002-0033-7514 ; 0000-0003-4924-1991</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.antiviral.2009.02.192$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21432443$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19428605$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02459207$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Paeshuyse, Jan</creatorcontrib><creatorcontrib>Letellier, Carine</creatorcontrib><creatorcontrib>Froeyen, Matheus</creatorcontrib><creatorcontrib>Dutartre, Hélène</creatorcontrib><creatorcontrib>Vrancken, Robert</creatorcontrib><creatorcontrib>Canard, Bruno</creatorcontrib><creatorcontrib>De Clercq, Erik</creatorcontrib><creatorcontrib>Gueiffier, Alain</creatorcontrib><creatorcontrib>Teulade, Jean-Claude</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><creatorcontrib>Puerstinger, Gerhard</creatorcontrib><creatorcontrib>Koenen, Frank</creatorcontrib><creatorcontrib>Kerkhofs, Pierre</creatorcontrib><creatorcontrib>Baraldi, Pier Giovanni</creatorcontrib><creatorcontrib>Neyts, Johan</creatorcontrib><title>A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase</title><title>Antiviral research</title><addtitle>Antiviral Res</addtitle><description>[7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of
in vitro bovine viral diarrhea virus (BVDV) replication. The EC
50 values for inhibition of BVDV-induced cytopathic effect (CPE) formation, viral RNA synthesis and production of infectious virus were 4.3
±
0.7
μM, 12.9
±
1
μM and 5.8
±
0.6
μM, respectively. LZ37 proved inactive against the hepatitis C virus and the flavivirus yellow fever. LZ37 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carried the F224Y mutation in the viral RNA-dependent RNA polymerase (RdRp). LZ37 showed cross-resistance with the imidazopyrrolopyridine AG110 [which selects for the E291G drug resistance mutation] as well as with the imidazopyridine BPIP [which selects for the F224S drug-resistant mutation]. LZ37 did not inhibit the
in vitro activity of purified recombinant BVDV RdRp. Molecular modelling revealed that F224 is located near the tip of the finger domain of the RdRp. Docking of LZ37 in the crystal structure of the BVDV RdRp revealed several potential contacts including: (i) hydrophobic contacts of LZ37 with A221, A222, G223, F224 and A392; (ii) a stacking interaction between F224 side chain and the ring system of LZ37 and (iii) a hydrogen bond between the amino function of LZ37 and the O backbone atom of A392. It is concluded that LZ37 interacts with the same binding site as BPIP or VP32947 at the top of the finger domain of the polymerase that is a “hot spot” for inhibition of pestivirus replication.</description><subject>Amino Acid Substitution - genetics</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Benzodioxoles - chemistry</subject><subject>Benzodioxoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bovine viral diarrhea virus</subject><subject>Cattle</subject><subject>Cell Line</subject><subject>Diarrhea Virus 1, Bovine Viral - drug effects</subject><subject>Diarrhea Virus 1, Bovine Viral - physiology</subject><subject>Diarrhea Virus 2, Bovine Viral - drug effects</subject><subject>Diarrhea Virus 2, Bovine Viral - physiology</subject><subject>Drug Resistance, Viral</subject><subject>Flavivirus</subject><subject>Hepacivirus - drug effects</subject><subject>Hepatitis C virus</subject><subject>Inhibitor</subject><subject>Inhibitory Concentration 50</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>Microbiology and Parasitology</subject><subject>Models, Molecular</subject><subject>Mutation, Missense</subject><subject>Pestivirus</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazolotriazolopyrimidinamine</subject><subject>RNA Replicase - chemistry</subject><subject>RNA Replicase - genetics</subject><subject>RNA-dependent RNA polymerase</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><subject>Viral Proteins - genetics</subject><subject>Virology</subject><subject>Virus Replication - drug effects</subject><subject>Yellow fever virus - drug effects</subject><issn>0166-3542</issn><issn>1872-9096</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcGO0zAQhi0EYsvCK0AuIHFIsB3HiY_RClikCiQEZ2viTKirJA62W6m8AW-Nsy3lyGn0j75_xuOfkFeMFowy-W5fwBzt0XoYC06pKigvmOKPyIY1Nc8VVfIx2SRS5mUl-A15FsKeUipr1TwlN0wJ3khabcjvNltOHn650UVvH2rSdrK9nWGyM2Z23tnORuczN2SdO669h8VZb8H7HcIqDyHzuIzWQLRuzuIOYhbB_8AYkvjr-Pq5zXtccO5xjqvKFjeeJvQQ8Dl5MsAY8MWl3pLvH95_u7vPt18-frprt7kRUsSc9w2vQdFaUtpzzhpTqloiBRAVHThFxbmB2hjowECPjWmkAKzEYFgnZFnekrfnuTsY9ZJOBX_SDqy-b7d67VEuKsVpfWSJfXNmF-9-HjBEPdlgcBxhRncImtOKs7KsElifQeNdCB6H62RG9ZqY3utrYnpNLK3RKbHkfHlZcegm7P_5LhEl4PUFgGBgHDzMxoYrx5kouRDrXe2Zw_R5R4teB2NxNthbjybq3tn_PuYPS4m7zQ</recordid><startdate>20090601</startdate><enddate>20090601</enddate><creator>Paeshuyse, Jan</creator><creator>Letellier, Carine</creator><creator>Froeyen, Matheus</creator><creator>Dutartre, Hélène</creator><creator>Vrancken, Robert</creator><creator>Canard, Bruno</creator><creator>De Clercq, Erik</creator><creator>Gueiffier, Alain</creator><creator>Teulade, Jean-Claude</creator><creator>Herdewijn, Piet</creator><creator>Puerstinger, Gerhard</creator><creator>Koenen, Frank</creator><creator>Kerkhofs, Pierre</creator><creator>Baraldi, Pier Giovanni</creator><creator>Neyts, Johan</creator><general>Elsevier B.V</general><general>Elsevier</general><general>Elsevier Masson</general><scope>IQODW</scope><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>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-0033-7514</orcidid><orcidid>https://orcid.org/0000-0003-4924-1991</orcidid></search><sort><creationdate>20090601</creationdate><title>A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase</title><author>Paeshuyse, Jan ; Letellier, Carine ; Froeyen, Matheus ; Dutartre, Hélène ; Vrancken, Robert ; Canard, Bruno ; De Clercq, Erik ; Gueiffier, Alain ; Teulade, Jean-Claude ; Herdewijn, Piet ; Puerstinger, Gerhard ; Koenen, Frank ; Kerkhofs, Pierre ; Baraldi, Pier Giovanni ; Neyts, Johan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c464t-2d827a907600d2218c3976e0aa450f20e922ca7ccabacade8c864ae54fc1b4633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Amino Acid Substitution - genetics</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Benzodioxoles - chemistry</topic><topic>Benzodioxoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bovine viral diarrhea virus</topic><topic>Cattle</topic><topic>Cell Line</topic><topic>Diarrhea Virus 1, Bovine Viral - drug effects</topic><topic>Diarrhea Virus 1, Bovine Viral - physiology</topic><topic>Diarrhea Virus 2, Bovine Viral - drug effects</topic><topic>Diarrhea Virus 2, Bovine Viral - physiology</topic><topic>Drug Resistance, Viral</topic><topic>Flavivirus</topic><topic>Hepacivirus - drug effects</topic><topic>Hepatitis C virus</topic><topic>Inhibitor</topic><topic>Inhibitory Concentration 50</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>Microbiology and Parasitology</topic><topic>Models, Molecular</topic><topic>Mutation, Missense</topic><topic>Pestivirus</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrazolotriazolopyrimidinamine</topic><topic>RNA Replicase - chemistry</topic><topic>RNA Replicase - genetics</topic><topic>RNA-dependent RNA polymerase</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacology</topic><topic>Viral Proteins - genetics</topic><topic>Virology</topic><topic>Virus Replication - drug effects</topic><topic>Yellow fever virus - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Paeshuyse, Jan</creatorcontrib><creatorcontrib>Letellier, Carine</creatorcontrib><creatorcontrib>Froeyen, Matheus</creatorcontrib><creatorcontrib>Dutartre, Hélène</creatorcontrib><creatorcontrib>Vrancken, Robert</creatorcontrib><creatorcontrib>Canard, Bruno</creatorcontrib><creatorcontrib>De Clercq, Erik</creatorcontrib><creatorcontrib>Gueiffier, Alain</creatorcontrib><creatorcontrib>Teulade, Jean-Claude</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><creatorcontrib>Puerstinger, Gerhard</creatorcontrib><creatorcontrib>Koenen, Frank</creatorcontrib><creatorcontrib>Kerkhofs, Pierre</creatorcontrib><creatorcontrib>Baraldi, Pier Giovanni</creatorcontrib><creatorcontrib>Neyts, Johan</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Antiviral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Paeshuyse, Jan</au><au>Letellier, Carine</au><au>Froeyen, Matheus</au><au>Dutartre, Hélène</au><au>Vrancken, Robert</au><au>Canard, Bruno</au><au>De Clercq, Erik</au><au>Gueiffier, Alain</au><au>Teulade, Jean-Claude</au><au>Herdewijn, Piet</au><au>Puerstinger, Gerhard</au><au>Koenen, Frank</au><au>Kerkhofs, Pierre</au><au>Baraldi, Pier Giovanni</au><au>Neyts, Johan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase</atitle><jtitle>Antiviral research</jtitle><addtitle>Antiviral Res</addtitle><date>2009-06-01</date><risdate>2009</risdate><volume>82</volume><issue>3</issue><spage>141</spage><epage>147</epage><pages>141-147</pages><issn>0166-3542</issn><eissn>1872-9096</eissn><coden>ARSRDR</coden><abstract>[7-[3-(1,3-Benzodioxol-5-yl)propyl]-2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] (LZ37) was identified as a selective inhibitor of
in vitro bovine viral diarrhea virus (BVDV) replication. The EC
50 values for inhibition of BVDV-induced cytopathic effect (CPE) formation, viral RNA synthesis and production of infectious virus were 4.3
±
0.7
μM, 12.9
±
1
μM and 5.8
±
0.6
μM, respectively. LZ37 proved inactive against the hepatitis C virus and the flavivirus yellow fever. LZ37 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carried the F224Y mutation in the viral RNA-dependent RNA polymerase (RdRp). LZ37 showed cross-resistance with the imidazopyrrolopyridine AG110 [which selects for the E291G drug resistance mutation] as well as with the imidazopyridine BPIP [which selects for the F224S drug-resistant mutation]. LZ37 did not inhibit the
in vitro activity of purified recombinant BVDV RdRp. Molecular modelling revealed that F224 is located near the tip of the finger domain of the RdRp. Docking of LZ37 in the crystal structure of the BVDV RdRp revealed several potential contacts including: (i) hydrophobic contacts of LZ37 with A221, A222, G223, F224 and A392; (ii) a stacking interaction between F224 side chain and the ring system of LZ37 and (iii) a hydrogen bond between the amino function of LZ37 and the O backbone atom of A392. It is concluded that LZ37 interacts with the same binding site as BPIP or VP32947 at the top of the finger domain of the polymerase that is a “hot spot” for inhibition of pestivirus replication.</abstract><cop>Kidlington</cop><pub>Elsevier B.V</pub><pmid>19428605</pmid><doi>10.1016/j.antiviral.2009.02.192</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-0033-7514</orcidid><orcidid>https://orcid.org/0000-0003-4924-1991</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0166-3542 |
| ispartof | Antiviral research, 2009-06, Vol.82 (3), p.141-147 |
| issn | 0166-3542 1872-9096 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_02459207v1 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Amino Acid Substitution - genetics Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemistry Antiviral Agents - pharmacology Benzodioxoles - chemistry Benzodioxoles - pharmacology Biological and medical sciences Bovine viral diarrhea virus Cattle Cell Line Diarrhea Virus 1, Bovine Viral - drug effects Diarrhea Virus 1, Bovine Viral - physiology Diarrhea Virus 2, Bovine Viral - drug effects Diarrhea Virus 2, Bovine Viral - physiology Drug Resistance, Viral Flavivirus Hepacivirus - drug effects Hepatitis C virus Inhibitor Inhibitory Concentration 50 Life Sciences Medical sciences Microbiology and Parasitology Models, Molecular Mutation, Missense Pestivirus Pharmacology. Drug treatments Pyrazolotriazolopyrimidinamine RNA Replicase - chemistry RNA Replicase - genetics RNA-dependent RNA polymerase Triazoles - chemistry Triazoles - pharmacology Viral Proteins - genetics Virology Virus Replication - drug effects Yellow fever virus - drug effects |
| title | A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T15%3A18%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20pyrazolotriazolopyrimidinamine%20inhibitor%20of%20bovine%20viral%20diarrhea%20virus%20replication%20that%20targets%20the%20viral%20RNA-dependent%20RNA%20polymerase&rft.jtitle=Antiviral%20research&rft.au=Paeshuyse,%20Jan&rft.date=2009-06-01&rft.volume=82&rft.issue=3&rft.spage=141&rft.epage=147&rft.pages=141-147&rft.issn=0166-3542&rft.eissn=1872-9096&rft.coden=ARSRDR&rft_id=info:doi/10.1016/j.antiviral.2009.02.192&rft_dat=%3Cproquest_hal_p%3E20521335%3C/proquest_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=20521335&rft_id=info:pmid/19428605&rft_els_id=S0166354209002332&rfr_iscdi=true |