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

Abstract 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 11 -acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC 50 0.06 µM) while exhibiting low cytotoxicity (CC 50 > 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 50 = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.

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Publication Details

Journal
Nature Communications
Published
2026-07-27
DOI
https://doi.org/10.1038/s41467-026-75835-7
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Ondřej Baszczyňski, Celine Fischer, Bruno Canard, Toni Luise Meister et al.
Nature Communications
PARP inhibition in cancer therapy
article

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

Ondřej Baszczyňski, Celine Fischer, Bruno Canard, Toni Luise Meister, María García-Alai, Susanne Pfefferle, Chris Meier, Maximilian Sandmann, Simon Sander, Barbara Selisko, Joanna M. Watt, David Ruiz‐Carrillo, Benedikt Ganter, Ralf Fliegert, Barry V. L. Potter, Sahra Tajdar, Marina Ocenas, Julia Berger, Neele Pekarek, Stefanie Etzold, Tidow Henning
article en

Abstract

Abstract 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 11 -acyloxybenzyl (AB)-masking groups yields a membrane permeable, lipophilic prodrug that inhibits SARS-CoV-2 in cell culture (EC 50 0.06 µM) while exhibiting low cytotoxicity (CC 50 > 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 50 = 0.03 µM), making it a membrane-permeable nucleotide-based prodrug against viral macrodomains.

Nature CommunicationsVol. 17(1)
Centre National de la Recherche Scientifique (FR), Universität Hamburg (DE), University of Oxford (GB), University Medical Center Hamburg-Eppendorf (DE), German Center for Infection Research (DE), European Molecular Biology Laboratory (DE), Architecture et Fonction des Macromolécules Biologiques (FR), Centre for Structural Systems Biology (DE), University of Bath (GB), Bernhard Nocht Institute for Tropical Medicine (DE)
Deutsches Zentrum für Infektionsforschung, Wellcome Trust, Deutsche Forschungsgemeinschaft, Griffith University, Rheinische Friedrich-Wilhelms-Universität Bonn, National Institutes of Health, University of California, San Francisco, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 12%
PARP inhibition in cancer therapy
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