Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin
The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In b...
Gespeichert in:
| Veröffentlicht in: | Nature structural & molecular biology 2021-03, Vol.28 (3), p.319-325 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 325 |
|---|---|
| container_issue | 3 |
| container_start_page | 319 |
| container_title | Nature structural & molecular biology |
| container_volume | 28 |
| creator | Yin, Wanchao Luan, Xiaodong Li, Zhihai Zhou, Ziwei Wang, Qingxing Gao, Minqi Wang, Xiaoxi Zhou, Fulai Shi, Jingjing You, Erli Liu, Mingliang Wang, Qingxia Jiang, Yi Jiang, Hualiang Xiao, Gengfu Zhang, Leike Yu, Xuekui Zhang, Shuyang Eric Xu, H. |
| description | The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
The antiparasitic drug suramin directly inhibits SARS-CoV-2 RNA-dependent RNA polymerase by blocking binding of the RNA template–primer duplex and entry of nucleotide triphosphate to the catalytic site. |
| doi_str_mv | 10.1038/s41594-021-00570-0 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2498480187</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A655717351</galeid><sourcerecordid>A655717351</sourcerecordid><originalsourceid>FETCH-LOGICAL-c586t-55d8121322cb3c638238b6f78c228d8d211081866d325700067ae8a9b6602eb13</originalsourceid><addsrcrecordid>eNp9kUFvFCEcxYnR2Fr9Ah4MiRd7oP6BgWGOm02tjY0mu-qVMAyzpZkZVmAS99vLurXNGmM4QOD3HjweQq8pXFDg6n2qqGgqAowSAFEDgSfolIpKkKZR4unDuuEn6EVKdwBMiJo_Ryecy7pSwE7Rp3WOs81zNANuTfIJ9yFiP9361mcfJhx6nG8dXi9Wa7IM3wnDq88LvA3DbnTRJIfbHU5FPvrpJXrWmyG5V_fzGfr24fLr8iO5-XJ1vVzcECuUzESITlFGOWO25VZyxbhqZV8ry5jqVMcoBUWVlB1nJRWArI1TpmmlBOZays_Qu4PvNoYfs0tZjz5ZNwxmcmFOmlWNKumoqgv69i_0LsxxKq_TTBRnVUMlH6mNGZz2Ux9yNHZvqheyfBmtudhfe_EPqozOjd6GyfW-7B8Jzo8EhcnuZ96YOSV9vV4ds-zA2hhSiq7X2-hHE3eagt63rQ9t69K2_t22hiJ6c59ubkfXPUj-1FsAfgBSOZo2Lj7G_4_tL_pbrpI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2500687046</pqid></control><display><type>article</type><title>Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Yin, Wanchao ; Luan, Xiaodong ; Li, Zhihai ; Zhou, Ziwei ; Wang, Qingxing ; Gao, Minqi ; Wang, Xiaoxi ; Zhou, Fulai ; Shi, Jingjing ; You, Erli ; Liu, Mingliang ; Wang, Qingxia ; Jiang, Yi ; Jiang, Hualiang ; Xiao, Gengfu ; Zhang, Leike ; Yu, Xuekui ; Zhang, Shuyang ; Eric Xu, H.</creator><creatorcontrib>Yin, Wanchao ; Luan, Xiaodong ; Li, Zhihai ; Zhou, Ziwei ; Wang, Qingxing ; Gao, Minqi ; Wang, Xiaoxi ; Zhou, Fulai ; Shi, Jingjing ; You, Erli ; Liu, Mingliang ; Wang, Qingxia ; Jiang, Yi ; Jiang, Hualiang ; Xiao, Gengfu ; Zhang, Leike ; Yu, Xuekui ; Zhang, Shuyang ; Eric Xu, H.</creatorcontrib><description>The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
The antiparasitic drug suramin directly inhibits SARS-CoV-2 RNA-dependent RNA polymerase by blocking binding of the RNA template–primer duplex and entry of nucleotide triphosphate to the catalytic site.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-021-00570-0</identifier><identifier>PMID: 33674802</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>101/28 ; 631/154 ; 631/535/1258 ; 82/80 ; 82/83 ; Animals ; Antiparasitic agents ; Antiviral Agents - chemistry ; Antiviral Agents - metabolism ; Antiviral Agents - pharmacology ; Binding Sites ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Catalytic Domain ; Chemical properties ; Chlorocebus aethiops ; Coronavirus RNA-Dependent RNA Polymerase - antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase - chemistry ; Coronavirus RNA-Dependent RNA Polymerase - metabolism ; Coronaviruses ; COVID-19 ; Cryoelectron Microscopy ; DNA-directed RNA polymerase ; Electron microscopy ; Enzyme binding ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Health aspects ; Inhibitors ; Life Sciences ; Membrane Biology ; Nucleotides ; Pandemics ; Pharmacology, Experimental ; Protein Conformation ; Protein Structure ; RNA polymerase ; RNA polymerases ; RNA, Viral - chemistry ; RNA, Viral - metabolism ; RNA-directed RNA polymerase ; SARS-CoV-2 - drug effects ; Severe acute respiratory syndrome coronavirus 2 ; Structure ; Suramin ; Suramin - chemistry ; Suramin - metabolism ; Suramin - pharmacology ; Suramin sodium ; Vero Cells ; Viral diseases ; Virus Replication - drug effects</subject><ispartof>Nature structural & molecular biology, 2021-03, Vol.28 (3), p.319-325</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-55d8121322cb3c638238b6f78c228d8d211081866d325700067ae8a9b6602eb13</citedby><cites>FETCH-LOGICAL-c586t-55d8121322cb3c638238b6f78c228d8d211081866d325700067ae8a9b6602eb13</cites><orcidid>0000-0002-1279-5432 ; 0000-0002-6829-8144 ; 0000-0002-1532-0029 ; 0000-0003-0656-6315 ; 0000-0002-6889-4907 ; 0000-0002-0723-1413 ; 0000-0002-2816-6243 ; 0000-0003-1028-1267 ; 0000-0002-4434-2040 ; 0000-0002-2593-2571</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/33674802$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yin, Wanchao</creatorcontrib><creatorcontrib>Luan, Xiaodong</creatorcontrib><creatorcontrib>Li, Zhihai</creatorcontrib><creatorcontrib>Zhou, Ziwei</creatorcontrib><creatorcontrib>Wang, Qingxing</creatorcontrib><creatorcontrib>Gao, Minqi</creatorcontrib><creatorcontrib>Wang, Xiaoxi</creatorcontrib><creatorcontrib>Zhou, Fulai</creatorcontrib><creatorcontrib>Shi, Jingjing</creatorcontrib><creatorcontrib>You, Erli</creatorcontrib><creatorcontrib>Liu, Mingliang</creatorcontrib><creatorcontrib>Wang, Qingxia</creatorcontrib><creatorcontrib>Jiang, Yi</creatorcontrib><creatorcontrib>Jiang, Hualiang</creatorcontrib><creatorcontrib>Xiao, Gengfu</creatorcontrib><creatorcontrib>Zhang, Leike</creatorcontrib><creatorcontrib>Yu, Xuekui</creatorcontrib><creatorcontrib>Zhang, Shuyang</creatorcontrib><creatorcontrib>Eric Xu, H.</creatorcontrib><title>Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
The antiparasitic drug suramin directly inhibits SARS-CoV-2 RNA-dependent RNA polymerase by blocking binding of the RNA template–primer duplex and entry of nucleotide triphosphate to the catalytic site.</description><subject>101/28</subject><subject>631/154</subject><subject>631/535/1258</subject><subject>82/80</subject><subject>82/83</subject><subject>Animals</subject><subject>Antiparasitic agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - metabolism</subject><subject>Antiviral Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Catalytic Domain</subject><subject>Chemical properties</subject><subject>Chlorocebus aethiops</subject><subject>Coronavirus RNA-Dependent RNA Polymerase - antagonists & inhibitors</subject><subject>Coronavirus RNA-Dependent RNA Polymerase - chemistry</subject><subject>Coronavirus RNA-Dependent RNA Polymerase - metabolism</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>Cryoelectron Microscopy</subject><subject>DNA-directed RNA polymerase</subject><subject>Electron microscopy</subject><subject>Enzyme binding</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Health aspects</subject><subject>Inhibitors</subject><subject>Life Sciences</subject><subject>Membrane Biology</subject><subject>Nucleotides</subject><subject>Pandemics</subject><subject>Pharmacology, Experimental</subject><subject>Protein Conformation</subject><subject>Protein Structure</subject><subject>RNA polymerase</subject><subject>RNA polymerases</subject><subject>RNA, Viral - chemistry</subject><subject>RNA, Viral - metabolism</subject><subject>RNA-directed RNA polymerase</subject><subject>SARS-CoV-2 - drug effects</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Structure</subject><subject>Suramin</subject><subject>Suramin - chemistry</subject><subject>Suramin - metabolism</subject><subject>Suramin - pharmacology</subject><subject>Suramin sodium</subject><subject>Vero Cells</subject><subject>Viral diseases</subject><subject>Virus Replication - drug effects</subject><issn>1545-9993</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kUFvFCEcxYnR2Fr9Ah4MiRd7oP6BgWGOm02tjY0mu-qVMAyzpZkZVmAS99vLurXNGmM4QOD3HjweQq8pXFDg6n2qqGgqAowSAFEDgSfolIpKkKZR4unDuuEn6EVKdwBMiJo_Ryecy7pSwE7Rp3WOs81zNANuTfIJ9yFiP9361mcfJhx6nG8dXi9Wa7IM3wnDq88LvA3DbnTRJIfbHU5FPvrpJXrWmyG5V_fzGfr24fLr8iO5-XJ1vVzcECuUzESITlFGOWO25VZyxbhqZV8ry5jqVMcoBUWVlB1nJRWArI1TpmmlBOZays_Qu4PvNoYfs0tZjz5ZNwxmcmFOmlWNKumoqgv69i_0LsxxKq_TTBRnVUMlH6mNGZz2Ux9yNHZvqheyfBmtudhfe_EPqozOjd6GyfW-7B8Jzo8EhcnuZ96YOSV9vV4ds-zA2hhSiq7X2-hHE3eagt63rQ9t69K2_t22hiJ6c59ubkfXPUj-1FsAfgBSOZo2Lj7G_4_tL_pbrpI</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Yin, Wanchao</creator><creator>Luan, Xiaodong</creator><creator>Li, Zhihai</creator><creator>Zhou, Ziwei</creator><creator>Wang, Qingxing</creator><creator>Gao, Minqi</creator><creator>Wang, Xiaoxi</creator><creator>Zhou, Fulai</creator><creator>Shi, Jingjing</creator><creator>You, Erli</creator><creator>Liu, Mingliang</creator><creator>Wang, Qingxia</creator><creator>Jiang, Yi</creator><creator>Jiang, Hualiang</creator><creator>Xiao, Gengfu</creator><creator>Zhang, Leike</creator><creator>Yu, Xuekui</creator><creator>Zhang, Shuyang</creator><creator>Eric Xu, H.</creator><general>Nature Publishing Group US</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>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PADUT</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1279-5432</orcidid><orcidid>https://orcid.org/0000-0002-6829-8144</orcidid><orcidid>https://orcid.org/0000-0002-1532-0029</orcidid><orcidid>https://orcid.org/0000-0003-0656-6315</orcidid><orcidid>https://orcid.org/0000-0002-6889-4907</orcidid><orcidid>https://orcid.org/0000-0002-0723-1413</orcidid><orcidid>https://orcid.org/0000-0002-2816-6243</orcidid><orcidid>https://orcid.org/0000-0003-1028-1267</orcidid><orcidid>https://orcid.org/0000-0002-4434-2040</orcidid><orcidid>https://orcid.org/0000-0002-2593-2571</orcidid></search><sort><creationdate>20210301</creationdate><title>Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin</title><author>Yin, Wanchao ; Luan, Xiaodong ; Li, Zhihai ; Zhou, Ziwei ; Wang, Qingxing ; Gao, Minqi ; Wang, Xiaoxi ; Zhou, Fulai ; Shi, Jingjing ; You, Erli ; Liu, Mingliang ; Wang, Qingxia ; Jiang, Yi ; Jiang, Hualiang ; Xiao, Gengfu ; Zhang, Leike ; Yu, Xuekui ; Zhang, Shuyang ; Eric Xu, H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c586t-55d8121322cb3c638238b6f78c228d8d211081866d325700067ae8a9b6602eb13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>101/28</topic><topic>631/154</topic><topic>631/535/1258</topic><topic>82/80</topic><topic>82/83</topic><topic>Animals</topic><topic>Antiparasitic agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - metabolism</topic><topic>Antiviral Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Catalytic Domain</topic><topic>Chemical properties</topic><topic>Chlorocebus aethiops</topic><topic>Coronavirus RNA-Dependent RNA Polymerase - antagonists & inhibitors</topic><topic>Coronavirus RNA-Dependent RNA Polymerase - chemistry</topic><topic>Coronavirus RNA-Dependent RNA Polymerase - metabolism</topic><topic>Coronaviruses</topic><topic>COVID-19</topic><topic>Cryoelectron Microscopy</topic><topic>DNA-directed RNA polymerase</topic><topic>Electron microscopy</topic><topic>Enzyme binding</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Health aspects</topic><topic>Inhibitors</topic><topic>Life Sciences</topic><topic>Membrane Biology</topic><topic>Nucleotides</topic><topic>Pandemics</topic><topic>Pharmacology, Experimental</topic><topic>Protein Conformation</topic><topic>Protein Structure</topic><topic>RNA polymerase</topic><topic>RNA polymerases</topic><topic>RNA, Viral - chemistry</topic><topic>RNA, Viral - metabolism</topic><topic>RNA-directed RNA polymerase</topic><topic>SARS-CoV-2 - drug effects</topic><topic>Severe acute respiratory syndrome coronavirus 2</topic><topic>Structure</topic><topic>Suramin</topic><topic>Suramin - chemistry</topic><topic>Suramin - metabolism</topic><topic>Suramin - pharmacology</topic><topic>Suramin sodium</topic><topic>Vero Cells</topic><topic>Viral diseases</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yin, Wanchao</creatorcontrib><creatorcontrib>Luan, Xiaodong</creatorcontrib><creatorcontrib>Li, Zhihai</creatorcontrib><creatorcontrib>Zhou, Ziwei</creatorcontrib><creatorcontrib>Wang, Qingxing</creatorcontrib><creatorcontrib>Gao, Minqi</creatorcontrib><creatorcontrib>Wang, Xiaoxi</creatorcontrib><creatorcontrib>Zhou, Fulai</creatorcontrib><creatorcontrib>Shi, Jingjing</creatorcontrib><creatorcontrib>You, Erli</creatorcontrib><creatorcontrib>Liu, Mingliang</creatorcontrib><creatorcontrib>Wang, Qingxia</creatorcontrib><creatorcontrib>Jiang, Yi</creatorcontrib><creatorcontrib>Jiang, Hualiang</creatorcontrib><creatorcontrib>Xiao, Gengfu</creatorcontrib><creatorcontrib>Zhang, Leike</creatorcontrib><creatorcontrib>Yu, Xuekui</creatorcontrib><creatorcontrib>Zhang, Shuyang</creatorcontrib><creatorcontrib>Eric Xu, H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</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>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</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>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Research Library China</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 Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature structural & molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yin, Wanchao</au><au>Luan, Xiaodong</au><au>Li, Zhihai</au><au>Zhou, Ziwei</au><au>Wang, Qingxing</au><au>Gao, Minqi</au><au>Wang, Xiaoxi</au><au>Zhou, Fulai</au><au>Shi, Jingjing</au><au>You, Erli</au><au>Liu, Mingliang</au><au>Wang, Qingxia</au><au>Jiang, Yi</au><au>Jiang, Hualiang</au><au>Xiao, Gengfu</au><au>Zhang, Leike</au><au>Yu, Xuekui</au><au>Zhang, Shuyang</au><au>Eric Xu, H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin</atitle><jtitle>Nature structural & molecular biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Mol Biol</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>28</volume><issue>3</issue><spage>319</spage><epage>325</epage><pages>319-325</pages><issn>1545-9993</issn><eissn>1545-9985</eissn><abstract>The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
The antiparasitic drug suramin directly inhibits SARS-CoV-2 RNA-dependent RNA polymerase by blocking binding of the RNA template–primer duplex and entry of nucleotide triphosphate to the catalytic site.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>33674802</pmid><doi>10.1038/s41594-021-00570-0</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-1279-5432</orcidid><orcidid>https://orcid.org/0000-0002-6829-8144</orcidid><orcidid>https://orcid.org/0000-0002-1532-0029</orcidid><orcidid>https://orcid.org/0000-0003-0656-6315</orcidid><orcidid>https://orcid.org/0000-0002-6889-4907</orcidid><orcidid>https://orcid.org/0000-0002-0723-1413</orcidid><orcidid>https://orcid.org/0000-0002-2816-6243</orcidid><orcidid>https://orcid.org/0000-0003-1028-1267</orcidid><orcidid>https://orcid.org/0000-0002-4434-2040</orcidid><orcidid>https://orcid.org/0000-0002-2593-2571</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1545-9993 |
| ispartof | Nature structural & molecular biology, 2021-03, Vol.28 (3), p.319-325 |
| issn | 1545-9993 1545-9985 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2498480187 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 101/28 631/154 631/535/1258 82/80 82/83 Animals Antiparasitic agents Antiviral Agents - chemistry Antiviral Agents - metabolism Antiviral Agents - pharmacology Binding Sites Biochemistry Biological Microscopy Biomedical and Life Sciences Catalytic Domain Chemical properties Chlorocebus aethiops Coronavirus RNA-Dependent RNA Polymerase - antagonists & inhibitors Coronavirus RNA-Dependent RNA Polymerase - chemistry Coronavirus RNA-Dependent RNA Polymerase - metabolism Coronaviruses COVID-19 Cryoelectron Microscopy DNA-directed RNA polymerase Electron microscopy Enzyme binding Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Health aspects Inhibitors Life Sciences Membrane Biology Nucleotides Pandemics Pharmacology, Experimental Protein Conformation Protein Structure RNA polymerase RNA polymerases RNA, Viral - chemistry RNA, Viral - metabolism RNA-directed RNA polymerase SARS-CoV-2 - drug effects Severe acute respiratory syndrome coronavirus 2 Structure Suramin Suramin - chemistry Suramin - metabolism Suramin - pharmacology Suramin sodium Vero Cells Viral diseases Virus Replication - drug effects |
| title | Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T20%3A11%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structural%20basis%20for%20inhibition%20of%20the%20SARS-CoV-2%20RNA%20polymerase%20by%20suramin&rft.jtitle=Nature%20structural%20&%20molecular%20biology&rft.au=Yin,%20Wanchao&rft.date=2021-03-01&rft.volume=28&rft.issue=3&rft.spage=319&rft.epage=325&rft.pages=319-325&rft.issn=1545-9993&rft.eissn=1545-9985&rft_id=info:doi/10.1038/s41594-021-00570-0&rft_dat=%3Cgale_proqu%3EA655717351%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2500687046&rft_id=info:pmid/33674802&rft_galeid=A655717351&rfr_iscdi=true |