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Front. Immunol., 06 January 2026
Sec. Viral Immunology
Volume 16 - 2025 | https://doi.org/10.3389/fimmu.2025.1706997
Acetylsalicylic acid disrupts SARS-CoV-2 spike protein glycosylation and selectively impairs binding to ACE2
Luca Perico*†Alessandra Bovio†Susanna TomasoniPiera TrionfiniDomenico CerulloDaniela CornaAnna PezzottaMonica LocatelliMarta AlbertiAriela BenigniGiuseppe Remuzzi- Department of Molecular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
Preclinical and clinical evidence suggested the potential benefits of treatment with acetylsalicylic acid (ASA) in mitigating COVID-19 severity. While available studies largely focused on the intracellular pathways through which ASA impairs viral replication or dampens host immunoresponse stimulated by SARS-CoV-2, whether ASA directly affects the interaction between the viral spike protein and its cellular receptor angiotensin converting enzyme 2 (ACE2) remains unexplored. This question is clinically relevant, as circulating spike S1 has been shown to persist in patients with acute and long COVID-19, where its interaction with the broadly expressed ACE2 drives systemic manifestations and tissue damage. Here, we demonstrate that pre-incubation of the SARS-CoV-2 spike subunit 1 (S1) with ASA dose-dependently impaired ACE2 binding on Vero cells. The functional relevance of this finding was confirmed in transgenic mice with human ACE2, in which intratracheal administration of ASA-treated S1 markedly reduced lung injury, fibrosis, and inflammation compared to untreated S1. Glycoproteomic profiling revealed that ASA altered the glycosylation landscape of S1, particularly N-glycosylation at N61 and O-glycosylation at S325. Site-directed mutagenesis of these two residues confirmed the critical role of their glycosylation in S1-ACE2 binding in vitro. Consistently, the glycosylation-insensitive S1 had limited effect in inducing lung injury, fibrosis, and inflammation in transgenic mice compared to WT S1, phenocopying the protective effects of ASA. These findings unveil a previously unrecognized antiviral activity of ASA, providing a molecular rationale for its repurposing as a low-cost, readily available intervention to prevent the progression from mild to severe COVID-19.
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To ensure clinical relevance, we used three different concentrations of ASA (5, 20, and 50 mg/L), in the range of plasma levels achievable with oral doses of 500–1000 mg ASA (58). As shown in Figure 1A, pre-treatment with ASA was able to significantly inhibit the binding of S1 to Vero cells in a dose-dependent manner. Of note, this inhibitory effect was not observed when S1 was incubated with another compound, namely paracetamol (Supplementary Figure 2), indicating the specific effect of ASA.
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MeSH Entry Terms for Aspirin
- Aspirin
- Acetylsalicylic Acid
- 2-(Acetyloxy)benzoic Acid
