Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2
Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyub...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Klemm, Theresa [verfasserIn] Ebert, Gregor [verfasserIn] Calleja, Dale J [verfasserIn] Allison, Cody C [verfasserIn] Richardson, Lachlan W [verfasserIn] Bernardini, Jonathan P [verfasserIn] Lu, Bernadine GC [verfasserIn] Kuchel, Nathan W [verfasserIn] Grohmann, Christoph [verfasserIn] Shibata, Yuri [verfasserIn] Gan, Zhong Yan [verfasserIn] Cooney, James P [verfasserIn] Doerflinger, Marcel [verfasserIn] Au, Amanda E [verfasserIn] Blackmore, Timothy R [verfasserIn] van der Heden van Noort, Gerbrand J [verfasserIn] Geurink, Paul P [verfasserIn] Ovaa, Huib [verfasserIn] Newman, Janet [verfasserIn] Riboldi‐Tunnicliffe, Alan [verfasserIn] Czabotar, Peter E [verfasserIn] Mitchell, Jeffrey P [verfasserIn] Feltham, Rebecca [verfasserIn] Lechtenberg, Bernhard C [verfasserIn] Lowes, Kym N [verfasserIn] Dewson, Grant [verfasserIn] Pellegrini, Marc [verfasserIn] Lessene, Guillaume [verfasserIn] Komander, David [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 39(2020), 18 vom: 26. Aug. |
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| Übergeordnetes Werk: |
volume:39 ; year:2020 ; number:18 ; day:26 ; month:08 |
| Links: |
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| DOI / URN: |
10.15252/embj.2020106275 |
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| Katalog-ID: |
SPR058018689 |
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| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
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| 024 | 7 | |a 10.15252/embj.2020106275 |2 doi | |
| 035 | |a (DE-627)SPR058018689 | ||
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Klemm, Theresa |e verfasserin |0 (orcid)0000-0002-2847-3550 |4 aut | |
| 245 | 1 | 0 | |a Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © The Author(s) 2020 | ||
| 520 | |a Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. | ||
| 520 | |a Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. | ||
| 520 | |a Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. | ||
| 650 | 4 | |a COVID‐19 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a ISG15 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a papain‐like protease |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a small molecule inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a ubiquitin |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Ebert, Gregor |e verfasserin |4 aut | |
| 700 | 1 | |a Calleja, Dale J |e verfasserin |0 (orcid)0000-0002-8306-0900 |4 aut | |
| 700 | 1 | |a Allison, Cody C |e verfasserin |4 aut | |
| 700 | 1 | |a Richardson, Lachlan W |e verfasserin |0 (orcid)0000-0001-8877-1376 |4 aut | |
| 700 | 1 | |a Bernardini, Jonathan P |e verfasserin |0 (orcid)0000-0002-5767-7624 |4 aut | |
| 700 | 1 | |a Lu, Bernadine GC |e verfasserin |0 (orcid)0000-0001-8044-9710 |4 aut | |
| 700 | 1 | |a Kuchel, Nathan W |e verfasserin |4 aut | |
| 700 | 1 | |a Grohmann, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Shibata, Yuri |e verfasserin |4 aut | |
| 700 | 1 | |a Gan, Zhong Yan |e verfasserin |0 (orcid)0000-0001-5755-7780 |4 aut | |
| 700 | 1 | |a Cooney, James P |e verfasserin |0 (orcid)0000-0003-3680-4644 |4 aut | |
| 700 | 1 | |a Doerflinger, Marcel |e verfasserin |0 (orcid)0000-0001-9159-3021 |4 aut | |
| 700 | 1 | |a Au, Amanda E |e verfasserin |0 (orcid)0000-0003-3656-2673 |4 aut | |
| 700 | 1 | |a Blackmore, Timothy R |e verfasserin |0 (orcid)0000-0001-7079-676X |4 aut | |
| 700 | 1 | |a van der Heden van Noort, Gerbrand J |e verfasserin |0 (orcid)0000-0001-5955-6431 |4 aut | |
| 700 | 1 | |a Geurink, Paul P |e verfasserin |4 aut | |
| 700 | 1 | |a Ovaa, Huib |e verfasserin |4 aut | |
| 700 | 1 | |a Newman, Janet |e verfasserin |0 (orcid)0000-0003-2666-3219 |4 aut | |
| 700 | 1 | |a Riboldi‐Tunnicliffe, Alan |e verfasserin |0 (orcid)0000-0003-2244-2486 |4 aut | |
| 700 | 1 | |a Czabotar, Peter E |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Jeffrey P |e verfasserin |4 aut | |
| 700 | 1 | |a Feltham, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Lechtenberg, Bernhard C |e verfasserin |0 (orcid)0000-0002-5674-6894 |4 aut | |
| 700 | 1 | |a Lowes, Kym N |e verfasserin |4 aut | |
| 700 | 1 | |a Dewson, Grant |e verfasserin |0 (orcid)0000-0003-4251-8898 |4 aut | |
| 700 | 1 | |a Pellegrini, Marc |e verfasserin |0 (orcid)0000-0003-3627-3126 |4 aut | |
| 700 | 1 | |a Lessene, Guillaume |e verfasserin |0 (orcid)0000-0002-1193-8147 |4 aut | |
| 700 | 1 | |a Komander, David |e verfasserin |0 (orcid)0000-0002-8092-4320 |4 aut | |
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| 912 | |a GBV_ILN_2048 | ||
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| 912 | |a GBV_ILN_2088 | ||
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| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2108 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2111 | ||
| 912 | |a GBV_ILN_2113 | ||
| 912 | |a GBV_ILN_2118 | ||
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10.15252/embj.2020106275 doi (DE-627)SPR058018689 (SPR)embj.2020106275-e DE-627 ger DE-627 rakwb eng Klemm, Theresa verfasserin (orcid)0000-0002-2847-3550 aut Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 Ebert, Gregor verfasserin aut Calleja, Dale J verfasserin (orcid)0000-0002-8306-0900 aut Allison, Cody C verfasserin aut Richardson, Lachlan W verfasserin (orcid)0000-0001-8877-1376 aut Bernardini, Jonathan P verfasserin (orcid)0000-0002-5767-7624 aut Lu, Bernadine GC verfasserin (orcid)0000-0001-8044-9710 aut Kuchel, Nathan W verfasserin aut Grohmann, Christoph verfasserin aut Shibata, Yuri verfasserin aut Gan, Zhong Yan verfasserin (orcid)0000-0001-5755-7780 aut Cooney, James P verfasserin (orcid)0000-0003-3680-4644 aut Doerflinger, Marcel verfasserin (orcid)0000-0001-9159-3021 aut Au, Amanda E verfasserin (orcid)0000-0003-3656-2673 aut Blackmore, Timothy R verfasserin (orcid)0000-0001-7079-676X aut van der Heden van Noort, Gerbrand J verfasserin (orcid)0000-0001-5955-6431 aut Geurink, Paul P verfasserin aut Ovaa, Huib verfasserin aut Newman, Janet verfasserin (orcid)0000-0003-2666-3219 aut Riboldi‐Tunnicliffe, Alan verfasserin (orcid)0000-0003-2244-2486 aut Czabotar, Peter E verfasserin aut Mitchell, Jeffrey P verfasserin aut Feltham, Rebecca verfasserin aut Lechtenberg, Bernhard C verfasserin (orcid)0000-0002-5674-6894 aut Lowes, Kym N verfasserin aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Pellegrini, Marc verfasserin (orcid)0000-0003-3627-3126 aut Lessene, Guillaume verfasserin (orcid)0000-0002-1193-8147 aut Komander, David verfasserin (orcid)0000-0002-8092-4320 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 18 vom: 26. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:18 day:26 month:08 https://dx.doi.org/10.15252/embj.2020106275 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 18 26 08 |
| spelling |
10.15252/embj.2020106275 doi (DE-627)SPR058018689 (SPR)embj.2020106275-e DE-627 ger DE-627 rakwb eng Klemm, Theresa verfasserin (orcid)0000-0002-2847-3550 aut Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 Ebert, Gregor verfasserin aut Calleja, Dale J verfasserin (orcid)0000-0002-8306-0900 aut Allison, Cody C verfasserin aut Richardson, Lachlan W verfasserin (orcid)0000-0001-8877-1376 aut Bernardini, Jonathan P verfasserin (orcid)0000-0002-5767-7624 aut Lu, Bernadine GC verfasserin (orcid)0000-0001-8044-9710 aut Kuchel, Nathan W verfasserin aut Grohmann, Christoph verfasserin aut Shibata, Yuri verfasserin aut Gan, Zhong Yan verfasserin (orcid)0000-0001-5755-7780 aut Cooney, James P verfasserin (orcid)0000-0003-3680-4644 aut Doerflinger, Marcel verfasserin (orcid)0000-0001-9159-3021 aut Au, Amanda E verfasserin (orcid)0000-0003-3656-2673 aut Blackmore, Timothy R verfasserin (orcid)0000-0001-7079-676X aut van der Heden van Noort, Gerbrand J verfasserin (orcid)0000-0001-5955-6431 aut Geurink, Paul P verfasserin aut Ovaa, Huib verfasserin aut Newman, Janet verfasserin (orcid)0000-0003-2666-3219 aut Riboldi‐Tunnicliffe, Alan verfasserin (orcid)0000-0003-2244-2486 aut Czabotar, Peter E verfasserin aut Mitchell, Jeffrey P verfasserin aut Feltham, Rebecca verfasserin aut Lechtenberg, Bernhard C verfasserin (orcid)0000-0002-5674-6894 aut Lowes, Kym N verfasserin aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Pellegrini, Marc verfasserin (orcid)0000-0003-3627-3126 aut Lessene, Guillaume verfasserin (orcid)0000-0002-1193-8147 aut Komander, David verfasserin (orcid)0000-0002-8092-4320 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 18 vom: 26. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:18 day:26 month:08 https://dx.doi.org/10.15252/embj.2020106275 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 18 26 08 |
| allfields_unstemmed |
10.15252/embj.2020106275 doi (DE-627)SPR058018689 (SPR)embj.2020106275-e DE-627 ger DE-627 rakwb eng Klemm, Theresa verfasserin (orcid)0000-0002-2847-3550 aut Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 Ebert, Gregor verfasserin aut Calleja, Dale J verfasserin (orcid)0000-0002-8306-0900 aut Allison, Cody C verfasserin aut Richardson, Lachlan W verfasserin (orcid)0000-0001-8877-1376 aut Bernardini, Jonathan P verfasserin (orcid)0000-0002-5767-7624 aut Lu, Bernadine GC verfasserin (orcid)0000-0001-8044-9710 aut Kuchel, Nathan W verfasserin aut Grohmann, Christoph verfasserin aut Shibata, Yuri verfasserin aut Gan, Zhong Yan verfasserin (orcid)0000-0001-5755-7780 aut Cooney, James P verfasserin (orcid)0000-0003-3680-4644 aut Doerflinger, Marcel verfasserin (orcid)0000-0001-9159-3021 aut Au, Amanda E verfasserin (orcid)0000-0003-3656-2673 aut Blackmore, Timothy R verfasserin (orcid)0000-0001-7079-676X aut van der Heden van Noort, Gerbrand J verfasserin (orcid)0000-0001-5955-6431 aut Geurink, Paul P verfasserin aut Ovaa, Huib verfasserin aut Newman, Janet verfasserin (orcid)0000-0003-2666-3219 aut Riboldi‐Tunnicliffe, Alan verfasserin (orcid)0000-0003-2244-2486 aut Czabotar, Peter E verfasserin aut Mitchell, Jeffrey P verfasserin aut Feltham, Rebecca verfasserin aut Lechtenberg, Bernhard C verfasserin (orcid)0000-0002-5674-6894 aut Lowes, Kym N verfasserin aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Pellegrini, Marc verfasserin (orcid)0000-0003-3627-3126 aut Lessene, Guillaume verfasserin (orcid)0000-0002-1193-8147 aut Komander, David verfasserin (orcid)0000-0002-8092-4320 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 18 vom: 26. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:18 day:26 month:08 https://dx.doi.org/10.15252/embj.2020106275 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 18 26 08 |
| allfieldsGer |
10.15252/embj.2020106275 doi (DE-627)SPR058018689 (SPR)embj.2020106275-e DE-627 ger DE-627 rakwb eng Klemm, Theresa verfasserin (orcid)0000-0002-2847-3550 aut Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 Ebert, Gregor verfasserin aut Calleja, Dale J verfasserin (orcid)0000-0002-8306-0900 aut Allison, Cody C verfasserin aut Richardson, Lachlan W verfasserin (orcid)0000-0001-8877-1376 aut Bernardini, Jonathan P verfasserin (orcid)0000-0002-5767-7624 aut Lu, Bernadine GC verfasserin (orcid)0000-0001-8044-9710 aut Kuchel, Nathan W verfasserin aut Grohmann, Christoph verfasserin aut Shibata, Yuri verfasserin aut Gan, Zhong Yan verfasserin (orcid)0000-0001-5755-7780 aut Cooney, James P verfasserin (orcid)0000-0003-3680-4644 aut Doerflinger, Marcel verfasserin (orcid)0000-0001-9159-3021 aut Au, Amanda E verfasserin (orcid)0000-0003-3656-2673 aut Blackmore, Timothy R verfasserin (orcid)0000-0001-7079-676X aut van der Heden van Noort, Gerbrand J verfasserin (orcid)0000-0001-5955-6431 aut Geurink, Paul P verfasserin aut Ovaa, Huib verfasserin aut Newman, Janet verfasserin (orcid)0000-0003-2666-3219 aut Riboldi‐Tunnicliffe, Alan verfasserin (orcid)0000-0003-2244-2486 aut Czabotar, Peter E verfasserin aut Mitchell, Jeffrey P verfasserin aut Feltham, Rebecca verfasserin aut Lechtenberg, Bernhard C verfasserin (orcid)0000-0002-5674-6894 aut Lowes, Kym N verfasserin aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Pellegrini, Marc verfasserin (orcid)0000-0003-3627-3126 aut Lessene, Guillaume verfasserin (orcid)0000-0002-1193-8147 aut Komander, David verfasserin (orcid)0000-0002-8092-4320 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 18 vom: 26. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:18 day:26 month:08 https://dx.doi.org/10.15252/embj.2020106275 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 18 26 08 |
| allfieldsSound |
10.15252/embj.2020106275 doi (DE-627)SPR058018689 (SPR)embj.2020106275-e DE-627 ger DE-627 rakwb eng Klemm, Theresa verfasserin (orcid)0000-0002-2847-3550 aut Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 Ebert, Gregor verfasserin aut Calleja, Dale J verfasserin (orcid)0000-0002-8306-0900 aut Allison, Cody C verfasserin aut Richardson, Lachlan W verfasserin (orcid)0000-0001-8877-1376 aut Bernardini, Jonathan P verfasserin (orcid)0000-0002-5767-7624 aut Lu, Bernadine GC verfasserin (orcid)0000-0001-8044-9710 aut Kuchel, Nathan W verfasserin aut Grohmann, Christoph verfasserin aut Shibata, Yuri verfasserin aut Gan, Zhong Yan verfasserin (orcid)0000-0001-5755-7780 aut Cooney, James P verfasserin (orcid)0000-0003-3680-4644 aut Doerflinger, Marcel verfasserin (orcid)0000-0001-9159-3021 aut Au, Amanda E verfasserin (orcid)0000-0003-3656-2673 aut Blackmore, Timothy R verfasserin (orcid)0000-0001-7079-676X aut van der Heden van Noort, Gerbrand J verfasserin (orcid)0000-0001-5955-6431 aut Geurink, Paul P verfasserin aut Ovaa, Huib verfasserin aut Newman, Janet verfasserin (orcid)0000-0003-2666-3219 aut Riboldi‐Tunnicliffe, Alan verfasserin (orcid)0000-0003-2244-2486 aut Czabotar, Peter E verfasserin aut Mitchell, Jeffrey P verfasserin aut Feltham, Rebecca verfasserin aut Lechtenberg, Bernhard C verfasserin (orcid)0000-0002-5674-6894 aut Lowes, Kym N verfasserin aut Dewson, Grant verfasserin (orcid)0000-0003-4251-8898 aut Pellegrini, Marc verfasserin (orcid)0000-0003-3627-3126 aut Lessene, Guillaume verfasserin (orcid)0000-0002-1193-8147 aut Komander, David verfasserin (orcid)0000-0002-8092-4320 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 18 vom: 26. Aug. (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:18 day:26 month:08 https://dx.doi.org/10.15252/embj.2020106275 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 18 26 08 |
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English |
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Enthalten in The EMBO Journal 39(2020), 18 vom: 26. Aug. volume:39 year:2020 number:18 day:26 month:08 |
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Enthalten in The EMBO Journal 39(2020), 18 vom: 26. Aug. volume:39 year:2020 number:18 day:26 month:08 |
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Article |
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findex.gbv.de |
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COVID‐19 ISG15 papain‐like protease small molecule inhibitor ubiquitin |
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The EMBO Journal |
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Klemm, Theresa @@aut@@ Ebert, Gregor @@aut@@ Calleja, Dale J @@aut@@ Allison, Cody C @@aut@@ Richardson, Lachlan W @@aut@@ Bernardini, Jonathan P @@aut@@ Lu, Bernadine GC @@aut@@ Kuchel, Nathan W @@aut@@ Grohmann, Christoph @@aut@@ Shibata, Yuri @@aut@@ Gan, Zhong Yan @@aut@@ Cooney, James P @@aut@@ Doerflinger, Marcel @@aut@@ Au, Amanda E @@aut@@ Blackmore, Timothy R @@aut@@ van der Heden van Noort, Gerbrand J @@aut@@ Geurink, Paul P @@aut@@ Ovaa, Huib @@aut@@ Newman, Janet @@aut@@ Riboldi‐Tunnicliffe, Alan @@aut@@ Czabotar, Peter E @@aut@@ Mitchell, Jeffrey P @@aut@@ Feltham, Rebecca @@aut@@ Lechtenberg, Bernhard C @@aut@@ Lowes, Kym N @@aut@@ Dewson, Grant @@aut@@ Pellegrini, Marc @@aut@@ Lessene, Guillaume @@aut@@ Komander, David @@aut@@ |
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2020-08-26T00:00:00Z |
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266022529 |
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SPR058018689 |
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englisch |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058018689</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065148.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2020106275</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058018689</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2020106275-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Klemm, Theresa</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-2847-3550</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">COVID‐19</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " 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Klemm, Theresa |
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Klemm, Theresa misc COVID‐19 misc ISG15 misc papain‐like protease misc small molecule inhibitor misc ubiquitin Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
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Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 COVID‐19 (dpeaa)DE-He213 ISG15 (dpeaa)DE-He213 papain‐like protease (dpeaa)DE-He213 small molecule inhibitor (dpeaa)DE-He213 ubiquitin (dpeaa)DE-He213 |
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Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
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Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
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Klemm, Theresa Ebert, Gregor Calleja, Dale J Allison, Cody C Richardson, Lachlan W Bernardini, Jonathan P Lu, Bernadine GC Kuchel, Nathan W Grohmann, Christoph Shibata, Yuri Gan, Zhong Yan Cooney, James P Doerflinger, Marcel Au, Amanda E Blackmore, Timothy R van der Heden van Noort, Gerbrand J Geurink, Paul P Ovaa, Huib Newman, Janet Riboldi‐Tunnicliffe, Alan Czabotar, Peter E Mitchell, Jeffrey P Feltham, Rebecca Lechtenberg, Bernhard C Lowes, Kym N Dewson, Grant Pellegrini, Marc Lessene, Guillaume Komander, David |
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mechanism and inhibition of the papain‐like protease, plpro, of sars‐cov‐2 |
| title_auth |
Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
| abstract |
Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. © The Author(s) 2020 |
| abstractGer |
Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. © The Author(s) 2020 |
| abstract_unstemmed |
Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model. Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy. Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model. © The Author(s) 2020 |
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Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 |
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| up_date |
2024-10-24T04:55:29.762Z |
| _version_ |
1813769858333016064 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058018689</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065148.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2020106275</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058018689</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2020106275-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Klemm, Theresa</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-2847-3550</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non‐covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self‐processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS‐CoV‐2 infection model.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Crystal structures explain the specificity of SARS‐CoV‐2 papain‐like protease, PLpro, for ISG15 and Lys48‐linked diubiquitin, and specific inhibition of PLpro by small molecules, shows strong antiviral effects. SARS‐CoV-2 PLpro preferentially cleaves ISG15 and also targets longer Lys48‐linked ubiquitin chains.Preference for ISG15 is provided by the S1 ubiquitin binding site in PLpro, while Lys48‐polyubiquitin specificity is provided by the S2 ubiquitin binding site.In a high‐throughput screen, FDA approved drugs and late stage clinical compounds are unable to inhibit PLpro in vitro.Known SARS PLpro inhibitors also target SARS2 PLpro and show anti‐viral efficacy.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Crystal structure and biochemical analysis explains the specificity of SARS‐CoV‐2 PLpro for ISG15 and longer Lys48‐linked ubiquitin chains leading to the identification of inhibitors that show promising antiviral activity in a SARS‐CoV‐2 infection model.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">COVID‐19</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " 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| score |
7.401908 |