Mitoxantrone modulates a glycosaminoglycan-spike complex to inhibit SARS-CoV-2 infection
Zhang, Q.; Radvak, P.; Lee, J.; Xu, Y.; Cao-Dao, V.; Xu, M.; Zheng, W.; Chen, C. Z.; Xie, H.; Ye, Y.
Show abstract
Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a spike-GAG complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar GAG-binding activities but with reduced affinity for DNA topoisomerase may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles 96%
- The SARS-CoV-2 multibasic cleavage site facilitates early serine protease-mediated entry into organoid-derived human airway cells 95%
- A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus 95%
Similar papers in this journal
- Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate 95%
- A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity 95%
- Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections 95%
Similar papers in this journal
- Ethacridine inhibits SARS-CoV-2 by inactivating viral particles in cellular models 97%
- NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner 96%
- Nasal delivery of single-domain antibodies improve symptoms of SARS-CoV-2 infection in an animal model 96%
Similar papers in this journal
- The sequence and structural integrity of the SARS-CoV-2 Spike protein transmembrane domain is crucial for viral entry 95%
- SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB 94%
- Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19 94%
Similar papers in this journal
- Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression 96%
- Identification of a SARS-CoV-2 host metalloproteinase-dependent entry pathway differentially used by SARS-CoV-2 and variants of concern Alpha, Delta, and Omicron 95%
- A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.