Concanavalin A targets phylogenetically conserved N-linked glycans on coronavirus spike proteins for broad-spectrum antiviral activity
Year: 2026
Type: article
Abstract: ABSTRACT The rapid evolution of SARS-CoV-2 variants, driven by antigenic drift in the spike glycoprotein, continues to undermine the efficacy of current vaccines and monoclonal antibody therapies. Targeting conserved features of the spike protein has been a major focus against coronavirus entry and the development of therapeutics. Here, we demonstrate that the plant lectin concanavalin A (ConA) broadly inhibits coronavirus entry through a conserved mechanism. With a combination of cell-cell fusion, pseudoviral entry, and authentic virus infection models, we show that ConA broadly inhibits coronavirus spike-mediated membrane fusion and viral entry. Biochemical analyses reveal that ConA targets two highly conserved N-glycosylation sites outside the receptor binding domain, flanking the S2′ cleavage site via its mannose-binding properties. This interaction sterically impedes proteolytic activation of the spike, a molecular step essential for membrane fusion. ConA exhibited nanomolar efficacy against hCoV-NL63 infections in vitro and significantly reduced viral load and mitigated lung pathology in hCoV-NL63-infected mice in vivo . Our findings reveal specific N-linked glycosylation sites as a major vulnerability of the spike and highlight ConA as a prototype for the development of lectin-based therapeutics against emerging coronavirus infections. IMPORTANCE The rapid evolution of SARS-CoV-2 variants, which evade current vaccines and therapeutics by altering epitopes on the spike protein, highlights a critical need for broad-spectrum antivirals. This study investigates concanavalin A (ConA), a legume lectin that targets highly conserved N-linked glycosylation sites on the spike protein, as a potential pan-coronavirus entry inhibitor. ConA broadly inhibits diverse coronaviruses by blocking spike-mediated membrane fusion. In contrast to previously reported antiviral lectins, ConA binds specifically to high-mannose oligosaccharides by targeting two phylogenetically conserved residues in the S2 subunit outside the receptor-binding domain. Consequently, ConA binding prevents the proteolytic activation of S2′ and effectively inhibits membrane fusion and coronavirus infection both in vitro and in vivo . This work identifies conserved N-glycosylation sites on the spike protein as stable, vulnerable targets for antiviral intervention, distinct from the variable epitopes recognized by antibodies. These findings indicate that lectins like ConA may provide a promising approach for developing effective antivirals against emerging coronaviruses.
Source: Journal of Virology
DOI: 10.1128/jvi.01679-25
Authors: Dekuan Guo, Shi Yu, Kaixiong Ma, Hua Tao, Qingxing Wang, Sirui Han, Qiangyun Ai, Huina Hu, Xiancai Ma, Geng Li, Shaobo Wang
Institutions: Guangzhou University of Chinese Medicine, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Laboratory, Guangzhou Medical University, Chinese Academy of Sciences, Wuhan Institute of Virology, University of Chinese Academy of Sciences
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7156207231