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One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS\u2010CoV\u20102). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti\u2010SARS\u2010CoV\u20102 effects by inhibiting the interaction between Kelch\u2010like ECH\u2010associated protein 1 (KEAP1) and nuclear factor erythroid 2\u2010related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on\u2010target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID\u201019 therapies.<\/jats:p>","DOI":"10.1002\/cmdc.202100732","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T07:27:44Z","timestamp":1643614064000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Andrographolide Derivatives Target the KEAP1\/NRF2 Axis and Possess Potent Anti\u2010SARS\u2010CoV\u20102 Activity"],"prefix":"10.1002","volume":"17","author":[{"given":"Bianca","family":"Schulte","sequence":"first","affiliation":[{"name":"Institute of Virology University Hospital Bonn  Venusberg-Campus 1 53127 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Environmental Research\u2013UFZ  Permoserstra\u00dfe 15 04318 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-706X","authenticated-orcid":false,"given":"Beate I.","family":"Escher","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Environmental Research\u2013UFZ  Permoserstra\u00dfe 15 04318 Leipzig Germany"},{"name":"Center for Applied Geoscience Eberhard Karls University T\u00fcbingen  72076 T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0242-5726","authenticated-orcid":false,"given":"Sophie","family":"Wittenburg","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4043-9686","authenticated-orcid":false,"given":"Matic","family":"Proj","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  A\u0161ker\u010deva cesta 7 1000 Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Wolf","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Lemke","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6489-2106","authenticated-orcid":false,"given":"Gregor","family":"Schnakenburg","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry University of Bonn  Gerhard-Domagk-Str. 1 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3370-4587","authenticated-orcid":false,"given":"Izidor","family":"Sosi\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  A\u0161ker\u010deva cesta 7 1000 Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-6390","authenticated-orcid":false,"given":"Hendrik","family":"Streeck","sequence":"additional","affiliation":[{"name":"Institute of Virology University Hospital Bonn  Venusberg-Campus 1 53127 Bonn Germany"},{"name":"German Center for Infection Research (DZIF)  Partner Site Bonn-Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0013-6624","authenticated-orcid":false,"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7897","authenticated-orcid":false,"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5638-1955","authenticated-orcid":false,"given":"Christian","family":"Steinebach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute University of Bonn  An der Immenburg 4 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"e_1_2_8_1_1","author":"Tran Q. 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