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Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp3]

ABSTRACT: Here we identify halofuginone, a Prolyl-tRNA Synthetase (PRS) inhibitors as a potent inhibitors of SARS-CoV-2 cellular entry and viral replication. To infect the host cell, the SARS-CoV-2 spike protein interacts with cell surface heparan sulfate (HS) and angiotensin-converting enzyme 2 (ACE2) through its Receptor Binding Domain. Removal of cell surface HS or blockade of HS biosynthesis represents a promising clinical target for treatment of SARS-CoV-2. In vitro studies confirm that halofuginone and PRS inhibitors prevent HS biosynthesis and thereby HS cell surface presentation and Spike protein binding. Halofuginone also suppresses authentic SARS-CoV-2 infection by inhibiting PRS activity, which decreases the translation efficiency of proline-rich HS biosynthetic enzymes and essential SARS-CoV-2 proteins after infection. Thus, halofuginone inhibits SARS-CoV-2 at both attachment and post-entry steps and blocks SARS-CoV-2 infection of human lung airway epithelial cells at low nanomolar concentrations. These findings support the use of halofuginone, an orally bioavailable anti-fibrotic and anti-inflammatory compound with encouraging clinical phase 1 safety data, as an antiviral drug to prevent SARS-CoV-2 infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166411 | GEO | 2023/08/28

REPOSITORIES: GEO

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Project description:Despite the clinical success of anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines by rapidly spreading SARS-CoV-2 variants has been compromised. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host’s immune response and attenuate antibody efficiency. However, it still remains unclear whether targeting glycosylation on spike can impair SARS-CoV-2 and its variants infectivity. Methods: To assess the binding ability of glycosylated or deglycosylated spike with ACE2, we performed flow cytometry, ELISA, and BioLayer Interferometry methods. Viral entry ability was determined by luciferase intensity, immunoblotting, and immunofluorescence assay. A genome-wide association study (GWAS) was performed to identify the relationship of STT3A and COVID-19 severity. N-glycosylation regulated by NF-kB/STT3A axis was investigated by knockdown approach, chromatin immunoprecipitation, and promoter assay. To specifically target SARS-CoV-2 infected cells, we developed an antibody-drug conjugate coupling non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) on inhibitory effects of SARS-CoV-2 infection. Results: We found receptor binding domain and three SARS-CoV-2 distinct surface Nglycosylation sites in 57,311 spikes retrieved from NCBI-Virus-database are highly evolutionarily conserved (99.67%) and involved in ACE2 interaction. We further identified STT3A as a key glycosyltransferase that catalyzed spike glycosylation and positively correlated with COVID-19 severity. Inhibition of STT3A by N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 and its variants (B.1.1.7, and B.1.351) infectivity. Most importantly, 4G10-ADC internalized SARS-CoV-2 infected cells and subsequently released NGI-1 to deglycosylate spike protein. Thereby, it reinforces the neutralizing abilities in antibodies, vaccines, or convalescent sera, inhibiting SARS-CoV-2 and its variants’ infectivity. Our results suggest targeting STT3A-mediated evolution conserved glycosylation via ADC can provide a widespread impact on SARS-CoV-2 variants infection. Together, we identified a novel deglycosylation method to eradicate SARS-CoV-2 variants infection.

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Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp3]

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