tetano
Editor, Senior Moderator
Nat Commun
. 2026 Jul 27;17(1):7416.
doi: 10.1038/s41467-026-75835-7.
Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2
Maximilian Sandmann[SUP] 1 [/SUP], Sahra Tajdar[SUP] 2 [/SUP], Simon Sander[SUP] 3 [/SUP], David Ruiz Carrillo[SUP] 4 [/SUP], Benedikt Ganter[SUP] 2 [/SUP], Celine Fischer[SUP] 2 [/SUP], Marina Ocenas[SUP] 1 [/SUP], Stefanie Etzold[SUP] 1 [/SUP], Neele Pekarek[SUP] 5 6 [/SUP], Julia Berger[SUP] 5 6 [/SUP], Toni Luise Meister[SUP] 6 7 8 [/SUP], Barbara Selisko[SUP] 9 [/SUP], Bruno Canard[SUP] 9 [/SUP], Joanna M Watt[SUP] 10 11 [/SUP], Ondřej Baszczyňski[SUP] 10 [/SUP], Barry Vl Potter[SUP] 10 11 [/SUP], Maria Garcia Alai[SUP] 4 [/SUP], Tidow Henning[SUP] 3 [/SUP], Pfefferle Susanne[SUP] 5 6 [/SUP], Chris Meier[SUP] 2 12 [/SUP], Ralf Fliegert[SUP] 13 [/SUP]
Affiliations
Enzymatically active macrodomains of (+)ss-RNA viruses mediate immune evasion by countering ADP-ribosylation and are therefore promising druggable targets. 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 β-methyl-GS-441524-diphosphate as nanomolar inhibitor that exhibits >1000-fold selectivity over human MacroD1 and MacroD2. Addition of C[SUB]11[/SUB]-acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC[SUB]50[/SUB] 0.06 µM) while exhibiting low cytotoxicity (CC[SUB]50[/SUB] > 50 µM). Replacement of the terminal methyl phosphate with an ethyl phosphonate increases stability of the prodrug with little effect on toxicity and antiviral potency (EC[SUB]50[/SUB] = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.
. 2026 Jul 27;17(1):7416.
doi: 10.1038/s41467-026-75835-7.
Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2
Maximilian Sandmann[SUP] 1 [/SUP], Sahra Tajdar[SUP] 2 [/SUP], Simon Sander[SUP] 3 [/SUP], David Ruiz Carrillo[SUP] 4 [/SUP], Benedikt Ganter[SUP] 2 [/SUP], Celine Fischer[SUP] 2 [/SUP], Marina Ocenas[SUP] 1 [/SUP], Stefanie Etzold[SUP] 1 [/SUP], Neele Pekarek[SUP] 5 6 [/SUP], Julia Berger[SUP] 5 6 [/SUP], Toni Luise Meister[SUP] 6 7 8 [/SUP], Barbara Selisko[SUP] 9 [/SUP], Bruno Canard[SUP] 9 [/SUP], Joanna M Watt[SUP] 10 11 [/SUP], Ondřej Baszczyňski[SUP] 10 [/SUP], Barry Vl Potter[SUP] 10 11 [/SUP], Maria Garcia Alai[SUP] 4 [/SUP], Tidow Henning[SUP] 3 [/SUP], Pfefferle Susanne[SUP] 5 6 [/SUP], Chris Meier[SUP] 2 12 [/SUP], Ralf Fliegert[SUP] 13 [/SUP]
Affiliations
- PMID: 42509248
- PMCID: PMC13408504
- DOI: 10.1038/s41467-026-75835-7
Enzymatically active macrodomains of (+)ss-RNA viruses mediate immune evasion by countering ADP-ribosylation and are therefore promising druggable targets. 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 β-methyl-GS-441524-diphosphate as nanomolar inhibitor that exhibits >1000-fold selectivity over human MacroD1 and MacroD2. Addition of C[SUB]11[/SUB]-acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC[SUB]50[/SUB] 0.06 µM) while exhibiting low cytotoxicity (CC[SUB]50[/SUB] > 50 µM). Replacement of the terminal methyl phosphate with an ethyl phosphonate increases stability of the prodrug with little effect on toxicity and antiviral potency (EC[SUB]50[/SUB] = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.