Dual engagement of Spike and ACE2 by annexin A5 contributes to pleiotropic SARS-CoV-2 inhibition.

ingentiumby ingentium

In Discovery Literature.

Publication date: Jun 20, 2026

COVID-19 is primarily a respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can enter host airway epithelial cells through angiotensin-converting enzyme 2 (ACE2) receptors. Emerging SARS-CoV-2 variants are a roadblock to irradicating the disease. Given recombinant human annexin A5 (Anx5) inhibits proinflammatory responses, improves survival in sepsis models and binds to several receptors and lipids, we hypothesized that Anx5 impedes SARS-CoV-2 viral entry and lessens disease severity. To assess SARS-CoV-2 Spike-receptor binding domain (RBD) and ACE2 interactions with Anx5, the recombinant proteins were expressed and isolated, and interactions were evaluated using solution NMR, microscale thermophoresis, steady-state fluorescence and size-exclusion chromatography coupled to multi-angle light scattering. Remarkably, we found that Anx5 binds to both the Spike-RBD and ACE2. Further, Anx5 induced extensive N-Spike-RBD amide resonance broadening, most concentrated in the region that engages with ACE2 and least enriched on the opposite face, highlighting the ACE2 interface as the primary site of Anx5 binding. Finally, we demonstrate that Anx5 inhibits SARS-CoV-2 pseudoviral entry and reduces viral burden while enhancing survival in SARS-CoV-2-infected mammalian cells. Collectively, our findings demonstrate that Anx5 directly engages both Spike-RBD and ACE2, inhibits SARS-CoV-2 pseudoviral entry and reduces viral burden while enhancing survival of infected mammalian cells, supporting further investigation of Anx5 as a multi-functional anti-SARS-CoV-2 therapeutic.

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Concepts Keywords
Chromatography ACE2
Coronavirus Annexin A5
Covid COVID-19
Host SARS-CoV-2
Lessens Spike-RBD

Semantics

Type Source Name
disease MESH COVID-19
disease MESH respiratory tract infection
disease MESH severe acute respiratory syndrome
disease MESH sepsis
disease MESH face
pathway REACTOME Reproduction
disease MESH included
drug DRUGBANK Angiotensin II
disease MESH acute respiratory distress syndrome
disease MESH infections
drug DRUGBANK Serine
disease MESH dissociation
disease MESH leukocytosis
disease MESH lymphopenia
disease MESH thrombocytopenia
drug DRUGBANK Prothrombin
disease MESH pneumonia
disease MESH pulmonary embolism
disease MESH septic shock
disease MESH embolus
disease MESH inflammation
drug DRUGBANK Phosphatidyl serine
drug DRUGBANK Calcium
drug DRUGBANK L-Leucine
disease MESH viral infection
disease MESH MST
disease MESH MALS
drug DRUGBANK Sodium lauryl sulfate
disease MESH SDS
drug DRUGBANK L-Cysteine
drug DRUGBANK Glutathione disulfide
drug DRUGBANK Glutathione
disease MESH GSH
drug DRUGBANK Fluorescein
disease MESH NHS
disease MESH MWs
pathway REACTOME Signal attenuation
disease MESH ~nM
disease MESH thrombophilia
disease MESH injury
disease MESH respiratory failure
disease MESH macrophage activation syndrome
disease MESH MAS
disease MESH aortic stenosis
disease MESH heart attack
pathway KEGG Viral replication
disease MESH death
pathway REACTOME Release
drug DRUGBANK Kanamycin
drug DRUGBANK Ampicillin
drug DRUGBANK Isopropyl beta-D-thiogalactopyranoside
drug DRUGBANK Biotin
drug DRUGBANK Thiamine
drug DRUGBANK Nitrogen
drug DRUGBANK Guanidine
drug DRUGBANK Tromethamine
drug DRUGBANK Imidazole
drug DRUGBANK Edetic Acid
drug DRUGBANK Urea
drug DRUGBANK Glycerin
drug DRUGBANK Flunarizine
disease MESH glass
drug DRUGBANK Coenzyme M
disease MESH DSS
drug DRUGBANK Benzylpenicillin
drug DRUGBANK Streptomycin
disease MESH FBS
drug DRUGBANK Phosphate ion
disease MESH PBS
drug DRUGBANK Magnesium
disease MESH strain
disease MESH ICH
drug DRUGBANK Glycine
drug DRUGBANK Proline

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