000475969 001__ 475969
000475969 005__ 20250715175653.0
000475969 0247_ $$2doi$$a10.3389/fchem.2022.832431
000475969 0247_ $$2datacite_doi$$a10.3204/PUBDB-2022-01546
000475969 0247_ $$2altmetric$$aaltmetric:126441860
000475969 0247_ $$2pmid$$a35480391
000475969 0247_ $$2WOS$$aWOS:000792403500001
000475969 0247_ $$2openalex$$aopenalex:W4223575819
000475969 037__ $$aPUBDB-2022-01546
000475969 041__ $$aEnglish
000475969 082__ $$a540
000475969 1001_ $$0P:(DE-H253)PIP1082863$$aEwert, Wiebke$$b0$$eCorresponding author
000475969 245__ $$aHydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease
000475969 260__ $$aLausanne$$bFrontiers Media$$c2022
000475969 3367_ $$2DRIVER$$aarticle
000475969 3367_ $$2DataCite$$aOutput Types/Journal article
000475969 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1675070625_9958
000475969 3367_ $$2BibTeX$$aARTICLE
000475969 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000475969 3367_ $$00$$2EndNote$$aJournal Article
000475969 520__ $$aThe papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site.
000475969 536__ $$0G:(DE-HGF)POF4-633$$a633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633)$$cPOF4-633$$fPOF IV$$x0
000475969 536__ $$0G:(DE-HGF)POF4-6G3$$a6G3 - PETRA III (DESY) (POF4-6G3)$$cPOF4-6G3$$fPOF IV$$x1
000475969 536__ $$0G:(DE-HGF)FISCOV$$aFISCOV - FISCOV Helmholtz large research infrastructures in the fight against epidemic outbreaks (FISCOV)$$cFISCOV$$x2
000475969 536__ $$0G:(GEPRIS)390715994$$aDFG project 390715994 - EXC 2056: CUI: Advanced Imaging of Matter (390715994)$$c390715994$$x3
000475969 588__ $$aDataset connected to CrossRef, Journals: bib-pubdb1.desy.de
000475969 693__ $$0EXP:(DE-H253)P-P11-20150101$$1EXP:(DE-H253)PETRAIII-20150101$$6EXP:(DE-H253)P-P11-20150101$$aPETRA III$$fPETRA Beamline P11$$x0
000475969 7001_ $$0P:(DE-H253)PIP1082033$$aGünther, Sebastian$$b1$$eCorresponding author
000475969 7001_ $$0P:(DE-HGF)0$$aMiglioli, Francesca$$b2
000475969 7001_ $$0P:(DE-H253)PIP1089186$$aFalke, Sven$$b3
000475969 7001_ $$0P:(DE-H253)PIP1082068$$aReinke, Patrick Y. A.$$b4
000475969 7001_ $$0P:(DE-H253)PIP1030856$$aNiebling, Stephan$$b5
000475969 7001_ $$0P:(DE-H253)PIP1088971$$aGuenther, Christian$$b6
000475969 7001_ $$0P:(DE-H253)PIP1015711$$aHan, Huijong$$b7
000475969 7001_ $$0P:(DE-H253)PIP1080622$$aSrinivasan, Vasundara$$b8
000475969 7001_ $$0P:(DE-H253)PIP1083097$$aBrognaro, Hévila$$b9
000475969 7001_ $$0P:(DE-H253)PIP1031014$$aLieske, Julia$$b10
000475969 7001_ $$0P:(DE-H253)PIP1022131$$aLorenzen, Kristina$$b11
000475969 7001_ $$0P:(DE-HGF)0$$aGarcia-Alai, Maria M.$$b12
000475969 7001_ $$0P:(DE-H253)PIP1002913$$aBetzel, Christian$$b13
000475969 7001_ $$0P:(DE-HGF)0$$aCarcelli, Mauro$$b14
000475969 7001_ $$0P:(DE-H253)PIP1032408$$aHinrichs, Winfried$$b15
000475969 7001_ $$0P:(DE-HGF)0$$aRogolino, Dominga$$b16
000475969 7001_ $$0P:(DE-H253)PIP1006208$$aMeents, Alke$$b17$$eLast author
000475969 773__ $$0PERI:(DE-600)2711776-5$$a10.3389/fchem.2022.832431$$gVol. 10, p. 832431$$p832431$$tFrontiers in Chemistry$$v10$$x2296-2646$$y2022
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/Admin-Meents.pdf
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/Admin-Meents.pdf?subformat=pdfa$$xpdfa
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/DataSheet1_Hydrazones%20and%20Thiosemicarbazones%20Targeting%20Protein-Protein-Interactions%20of%20SARS-CoV-2%20Papain-like%20Protease.pdf$$yRestricted
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/fchem-10-832431.pdf$$yOpenAccess
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/DataSheet1_Hydrazones%20and%20Thiosemicarbazones%20Targeting%20Protein-Protein-Interactions%20of%20SARS-CoV-2%20Papain-like%20Protease.pdf?subformat=pdfa$$xpdfa$$yRestricted
000475969 8564_ $$uhttps://bib-pubdb1.desy.de/record/475969/files/fchem-10-832431.pdf?subformat=pdfa$$xpdfa$$yOpenAccess
000475969 8767_ $$82021-0525222-2$$92022-02-28$$d2022-03-16$$eAPC$$jZahlung erfolgt$$zWährung anpssen, Rechnung wurde nicht über L abgewickelt
000475969 909CO $$ooai:bib-pubdb1.desy.de:475969$$pdnbdelivery$$popenCost$$pVDB$$pdriver$$pOpenAPC$$popen_access$$popenaire
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1082863$$aDeutsches Elektronen-Synchrotron$$b0$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1082863$$aCentre for Free-Electron Laser Science$$b0$$kCFEL
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-H253)PIP1082863$$aEuropean Molecular Biology Laboratory$$b0$$kEMBL
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1082033$$aDeutsches Elektronen-Synchrotron$$b1$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1082033$$aCentre for Free-Electron Laser Science$$b1$$kCFEL
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1082033$$aEuropean XFEL$$b1$$kXFEL.EU
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1089186$$aDeutsches Elektronen-Synchrotron$$b3$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1089186$$aCentre for Free-Electron Laser Science$$b3$$kCFEL
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-H253)PIP1089186$$aEuropean Molecular Biology Laboratory$$b3$$kEMBL
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1082068$$aDeutsches Elektronen-Synchrotron$$b4$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1082068$$aCentre for Free-Electron Laser Science$$b4$$kCFEL
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1030856$$aCentre for Free-Electron Laser Science$$b5$$kCFEL
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-H253)PIP1030856$$aEuropean Molecular Biology Laboratory$$b5$$kEMBL
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1030856$$aExternal Institute$$b5$$kExtern
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1088971$$aExternal Institute$$b6$$kExtern
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1015711$$aEuropean XFEL$$b7$$kXFEL.EU
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-H253)PIP1080622$$aEuropean Molecular Biology Laboratory$$b8$$kEMBL
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1080622$$aExternal Institute$$b8$$kExtern
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-H253)PIP1083097$$aEuropean Molecular Biology Laboratory$$b9$$kEMBL
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1083097$$aEuropean XFEL$$b9$$kXFEL.EU
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1083097$$aExternal Institute$$b9$$kExtern
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1031014$$aDeutsches Elektronen-Synchrotron$$b10$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1031014$$aCentre for Free-Electron Laser Science$$b10$$kCFEL
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1031014$$aEuropean XFEL$$b10$$kXFEL.EU
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1022131$$aEuropean XFEL$$b11$$kXFEL.EU
000475969 9101_ $$0I:(DE-588b)235011-7$$6P:(DE-HGF)0$$aEuropean Molecular Biology Laboratory$$b12$$kEMBL
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1002913$$aExternal Institute$$b13$$kExtern
000475969 9101_ $$0I:(DE-HGF)0$$6P:(DE-H253)PIP1032408$$aExternal Institute$$b15$$kExtern
000475969 9101_ $$0I:(DE-588b)2008985-5$$6P:(DE-H253)PIP1006208$$aDeutsches Elektronen-Synchrotron$$b17$$kDESY
000475969 9101_ $$0I:(DE-H253)_CFEL-20120731$$6P:(DE-H253)PIP1006208$$aCentre for Free-Electron Laser Science$$b17$$kCFEL
000475969 9101_ $$0I:(DE-588)1043621512$$6P:(DE-H253)PIP1006208$$aEuropean XFEL$$b17$$kXFEL.EU
000475969 9131_ $$0G:(DE-HGF)POF4-633$$1G:(DE-HGF)POF4-630$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lFrom Matter to Materials and Life$$vLife Sciences – Building Blocks of Life: Structure and Function$$x0
000475969 9131_ $$0G:(DE-HGF)POF4-6G3$$1G:(DE-HGF)POF4-6G0$$2G:(DE-HGF)POF4-600$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bForschungsbereich Materie$$lGroßgeräte: Materie$$vPETRA III (DESY)$$x1
000475969 9141_ $$y2022
000475969 915pc $$0PC:(DE-HGF)0000$$2APC$$aAPC keys set
000475969 915pc $$0PC:(DE-HGF)0001$$2APC$$aLocal Funding
000475969 915pc $$0PC:(DE-HGF)0002$$2APC$$aDFG OA Publikationskosten
000475969 915pc $$0PC:(DE-HGF)0003$$2APC$$aDOAJ Journal
000475969 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-02-04
000475969 915__ $$0LIC:(DE-HGF)CCBY4$$2HGFVOC$$aCreative Commons Attribution CC BY 4.0
000475969 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bFRONT CHEM : 2019$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)9900$$2StatID$$aIF < 5$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000475969 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Blind peer review$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)1150$$2StatID$$aDBCoverage$$bCurrent Contents - Physical, Chemical and Earth Sciences$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0320$$2StatID$$aDBCoverage$$bPubMed Central$$d2021-02-04
000475969 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2021-02-04
000475969 9201_ $$0I:(DE-H253)FS-CFEL-1-BMX-20210408$$kFS-CFEL-1-BMX$$lFS-CFEL-1 Fachgruppe BMX$$x0
000475969 980__ $$ajournal
000475969 980__ $$aVDB
000475969 980__ $$aI:(DE-H253)FS-CFEL-1-BMX-20210408
000475969 980__ $$aAPC
000475969 980__ $$aUNRESTRICTED
000475969 9801_ $$aAPC
000475969 9801_ $$aFullTexts