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<p>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 &gt;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> &gt; 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.</p>

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Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月27日

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  • Maximilian Sandmann,
  • Sahra Tajdar,
  • Simon Sander,
  • David Ruiz Carrillo,
  • Benedikt Ganter,
  • Celine Fischer,
  • Marina Ocenas,
  • Stefanie Etzold,
  • Neele Pekarek,
  • Julia Berger,
  • Toni Luise Meister,
  • Barbara Selisko,
  • Bruno Canard,
  • Joanna M. Watt,
  • Ondřej Baszczyňski,
  • Barry VL Potter,
  • Maria Garcia Alai,
  • Tidow Henning,
  • Pfefferle Susanne,
  • Chris Meier,
  • Ralf Fliegert

摘要

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 C11-acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC50 0.06 µM) while exhibiting low cytotoxicity (CC50 > 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 (EC50 = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.