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ACS Sens ; 7(5): 1564-1571, 2022 05 27.
Article in English | MEDLINE | ID: covidwho-1795845


Nucleoside analogues are reagents that resemble the structure of natural nucleosides and are widely applied in antiviral and anticancer therapy. Molnupiravir, a recently reported nucleoside analogue drug, has shown its inhibitory effect against SARS-CoV-2. Rapid tracing of molnupiravir and its metabolites is important in the evaluation of its pharmacology effect, but direct sensing of molnupiravir as a single molecule has not been reported to date. Here, we demonstrate a nanopore-based sensor with which direct sensing of molnupiravir and its two major metabolites ß-d-N4-hydroxycytidine and its triphosphate can be achieved simultaneously. In conjunction with a custom machine learning algorithm, an accuracy of 92% was achieved. This sensing strategy may be useful in the current pandemic and is in principle suitable for other nucleoside analogue drugs.

COVID-19 Drug Treatment , Nanopores , Cytidine/analogs & derivatives , Humans , Hydroxylamines , Nucleosides , SARS-CoV-2
Proc Natl Acad Sci U S A ; 117(50): 32105-32113, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-947594


Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

COVID-19 Drug Treatment , Endosomes/genetics , Hydroxycholesterols/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Antiviral Agents/pharmacology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Endosomes/metabolism , Humans , Interferons/metabolism , Membrane Fusion/drug effects , Severe acute respiratory syndrome-related coronavirus/drug effects , Severe acute respiratory syndrome-related coronavirus/metabolism , Severe acute respiratory syndrome-related coronavirus/pathogenicity , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization/drug effects , Virus Replication/drug effects