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bioRxiv · 10.1101/2020.06.08.141077

Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Ding, S.·Zang, R.·Case, J. B.·Gomez Castro, M. F.·Liu, Z.·Zeng, Q.·Zhao, H.·Son, J.·Rothlauf, P. W.·Hou, G.·Bose, S.·Wang, X.·Vahey, M. D.·Kirchhausen, T.·Fremont, D. H.·Diamond, M. S.·Whelan, S. P. J.
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Abstract

Cholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene (ISG) that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an ISG screen against VSV-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of virus replication. Mechanistically, internalized 25HC accumulates in the late endosomes and blocks cholesterol export, thereby restricting SARS-CoV-2 spike protein catalyzed membrane fusion. Our results highlight a unique antiviral mechanism of 25HC and provide the molecular basis for its possible therapeutic development.

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Ding, S., Zang, R., Case, J. B., Gomez Castro, M. F., Liu, Z., Zeng, Q., Zhao, H., Son, J., Rothlauf, P. W., Hou, G., Bose, S., Wang, X., Vahey, M. D., Kirchhausen, T., Fremont, D. H., Diamond, M. S., Whelan, S. P. J.. 2020-06-09. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. https://doi.org/10.1101/2020.06.08.141077

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