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Here we report testing of ADP \/ ADP-ribose analogues for their ability to inhibit Mac1 of SARS-CoV-2, measurement of the affinity of active compounds and characterization of their binding mode by cocrystallization, uncovering critical molecular determinants of protein-ligand interaction. Key findings of the resulting structure-activity relationship (SAR) include that inhibitory potency is improved by either replacing the distal ribose of ADP-ribose by a small alkyl group or the adenine N7 by carbon. Based on insights from the SAR, we show \u03b2-methyl-GS-441524-diphosphate as nanomolar inhibitor that exhibits &gt;1000-fold selectivity over human MacroD1 and MacroD2. Addition of C\n                    <jats:sub>11<\/jats:sub>\n                    -acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC\n                    <jats:sub>50<\/jats:sub>\n                    0.06\u2009\u00b5M) while exhibiting low cytotoxicity (CC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&gt;\u200950\u2009\u00b5M). Replacement of the terminal methyl phosphate with an ethyl phosphonate increases stability of the prodrug with little effect on toxicity and antiviral potency (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.03\u2009\u00b5M), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-75835-7","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T15:44:53Z","timestamp":1785167093000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5741-6629","authenticated-orcid":false,"given":"Maximilian","family":"Sandmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahra","family":"Tajdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7985-2526","authenticated-orcid":false,"given":"Simon","family":"Sander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ruiz Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Ganter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ocenas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Etzold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neele","family":"Pekarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5857-4386","authenticated-orcid":false,"given":"Julia","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8962-9443","authenticated-orcid":false,"given":"Toni Luise","family":"Meister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Selisko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-1991","authenticated-orcid":false,"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna M.","family":"Watt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0195-9953","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Baszczy\u0148ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3255-9135","authenticated-orcid":false,"given":"Barry VL","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-7816","authenticated-orcid":false,"given":"Maria","family":"Garcia Alai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Tidow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-6557","authenticated-orcid":false,"given":"Susanne","family":"Pfefferle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-673X","authenticated-orcid":false,"given":"Ralf","family":"Fliegert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"75835_CR1","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1038\/sj.emboj.7600664","volume":"24","author":"GI Karras","year":"2005","unstructured":"Karras, G. 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