Acetylsalicylic acid disrupts SARS-CoV-2 spike protein glycosylation and selectively impairs binding to ACE2

Luca Perico; Alessandra Bovio; Susanna Tomasoni; Piera Trionfini; Domenico Cerullo; Daniela Corna; Anna Pezzotta; Monica Locatelli; Marta Alberti; Ariela Benigni; Giuseppe Remuzzi

Luca Perico, Alessandra Bovio, Susanna Tomasoni, Piera Trionfini, Domenico Cerullo, Daniela Corna, Anna Pezzotta, Monica Locatelli, Marta Alberti, Ariela Benigni, Giuseppe Remuzzi

Frontiers in Immunology, doi:10.3389/fimmu.2025.1706997

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.

Ethics statement Ethical approval was not required for the studies on humans in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used. The animal study was approved by Italian Ministry of Health (approval number 371/2023-PR). The study was conducted in accordance with the local legislation and institutional requirements. Author contributions Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI statement The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found..

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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\n in vitro\n . 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.\n ", "alternative-id": [ "10.3389/fimmu.2025.1706997" ], "article-number": "1706997", "author": [ { "affiliation": [], "family": "Perico", "given": "Luca", "sequence": "first" }, { "affiliation": [], "family": "Bovio", "given": "Alessandra", "sequence": "additional" }, { "affiliation": [], "family": "Tomasoni", "given": "Susanna", "sequence": "additional" }, { "affiliation": [], "family": "Trionfini", "given": "Piera", "sequence": "additional" }, { "affiliation": [], "family": "Cerullo", "given": "Domenico", "sequence": "additional" }, { "affiliation": [], "family": "Corna", "given": "Daniela", "sequence": "additional" }, { "affiliation": [], "family": "Pezzotta", "given": "Anna", "sequence": "additional" }, { "affiliation": [], "family": "Locatelli", "given": "Monica", "sequence": "additional" }, { "affiliation": [], "family": "Alberti", "given": "Marta", "sequence": "additional" }, { "affiliation": [], "family": "Benigni", "given": "Ariela", "sequence": "additional" }, { "affiliation": [], "family": "Remuzzi", "given": "Giuseppe", "sequence": "additional" } ], "container-title": "Frontiers in Immunology", "container-title-short": "Front. 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