Structure‐Based Rational Design of a Selective Hydrolase Inhibitor of the Severe Acute Respiratory Syndrome Coronavirus‐2 Nsp3 Macrodomain
Viral macrodomains, which hydrolyze mono-ADP-ribosylated proteins to evade host immunity, represent emerging antiviral targets, yet their druggability remains underexplored. GS-441524, the active metabolite of remdesivir, has been identified as an inhibitor of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) macrodomain (Nsp3b). Herein, the structure-activity relationship governing macrodomain recognition by the ribosylated moiety using a panel of nucleoside analogs, revealing that phosphate configuration and nucleobase identity critically modulate binding affinity. GS-441524 derivatives exhibit up to 200-fold higher affinity compared to adenosine-based ligands. A novel sulfamoyl derivative demonstrates superior inhibitory potency, attributable to its occupation of the phosphate subsite and formation of a stabilizing hydrogen-bond network. These findings provide molecular insights into Nsp3b-ligand interactions and establish a rational framework for the development of high-affinity, structure-guided inhibitors targeting viral macrodomains.
Authors
- F. Lennartz (ORCID: https://orcid.org/0000-0001-5617-5502)
- Nikolaos K. Fourkiotis (ORCID: https://orcid.org/0000-0002-5197-4142)
- Robin Krishnathas
- Harald Schwalbe (ORCID: https://orcid.org/0000-0001-5693-7909)
- Aikaterini C. Tsika (ORCID: https://orcid.org/0000-0002-3723-0606)
- M.S. Weiss (ORCID: https://orcid.org/0000-0002-2362-7047)
- Christos Sideras‐Bisdekis (ORCID: https://orcid.org/0000-0003-1347-4240)
- Georgios A. Spyroulias (ORCID: https://orcid.org/0000-0003-1799-3312)
- V.L. Linhard (ORCID: https://orcid.org/0000-0002-0278-9792)
- Sridhar Sreeramulu (ORCID: https://orcid.org/0000-0003-4509-4568)
- Franck Touret (ORCID: https://orcid.org/0000-0002-4734-2249)
- S.L. Gande
- Константин С. Минеев (ORCID: https://orcid.org/0000-0002-2418-9421)
- Bruno Coutard (ORCID: https://orcid.org/0000-0002-2859-7123)
Institutions
- Goethe University Frankfurt (DE)
- Inserm (FR)
- University of Patras (GR)
- Aix-Marseille Université (FR)
- Helmholtz-Zentrum Berlin für Materialien und Energie (DE)
- Institut de Recherche pour le Développement (FR)
Publication Details
- Journal
- ChemBioChem
- Published
- 2025-11-02
- DOI
- https://doi.org/10.1002/cbic.202500593
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Infrastructures en Biologie Santé et Agronomie
- European Commission
- Deutsche Forschungsgemeinschaft
- Directorate-General for Research and Innovation
- European Regional Development Fund