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Mitoxantrone modulates a glycosaminoglycan-spike complex to inhibit SARS-CoV-2 infection
Qi Zhang; Peter Radvak; Juhyung Lee; Yue Xu; Vivian Cao-Dao; Miao Xu; Wei Zheng; Catherine Z Chen; Hang Xie; Yihong Ye.
Afiliação
  • Qi Zhang; NIH/NCATS
  • Peter Radvak; Center for Biologics Evaluation and Research, US Food and Drug Administration
  • Juhyung Lee; NIH/NIDDK
  • Yue Xu; NIH/NIDDK
  • Vivian Cao-Dao; NIH/NIDDK
  • Miao Xu; NIH/NCATS
  • Wei Zheng; NIH/NCATS
  • Catherine Z Chen; NIH/NCATS
  • Hang Xie; Center for Biologics Evaluation and Research, US Food and Drug Administration
  • Yihong Ye; NIH/NIDDK
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-464595
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.
Licença
cc0
Texto completo: Disponível Coleções: Preprints Base de dados: bioRxiv Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Preprint
Texto completo: Disponível Coleções: Preprints Base de dados: bioRxiv Idioma: Inglês Ano de publicação: 2021 Tipo de documento: Preprint
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