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SARS-CoV-2 proteins

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    Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2

    Authors: Tianling Ou; Huihui Mou; Lizhou Zhang; Amrita Ojha; Hyeryun Choe; Michael Farzan

    doi:10.1101/2020.07.22.216150 Date: 2020-07-22 Source: bioRxiv

    Hydroxychloroquine, used to treat malaria MESHD and some autoimmune disorders MESHD, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 MESHD in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19 MESHD. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L HGNC can cleave the SARS-CoV-1 and SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN ( S) proteins PROTEIN, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 HGNC can similarly cleave these S proteins PROTEIN and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 HGNC expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein PROTEIN is ablated. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L HGNC, but not by TMPRSS2 HGNC, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 HGNC inhibitor prevents SARS-CoV-2 infection MESHD more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19 MESHD. Author SummaryThe novel pathogenic coronavirus SARS-CoV-2 causes COVID-19 MESHD and remains a threat to global public health. Chloroquine and hydroxychloroquine have been shown to prevent viral infection in cell-culture systems, but human clinical trials did not observe a significant improvement in COVID-19 MESHD patients treated with these compounds. Here we show that hydroxychloroquine interferes with only one of two somewhat redundant pathways by which the SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN is activated to mediate infection. The first pathway is dependent on the endosomal protease cathepsin L HGNC and sensitive to hydroxychloroquine, whereas the second pathway is dependent on TMPRSS2 HGNC, which is unaffected by this compound. We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 HGNC pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein PROTEIN. Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 HGNC inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 HGNC expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack of in vivo efficacy.

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MeSH Disease
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