Authors
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
Published in
Nature communications. Volume 17. Issue 1. Jul 27, 2026. Epub Jul 27, 2026.
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 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.
PMID:
42509248
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.
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