Vitamin C is an efficient natural product for prevention of SARS-CoV-2 infection by targeting ACE2 in both cell and in vivo mouse models

Zuo, Y.; Zheng, Z.; Huang, Y.; He, J.; Zang, L.; Ren, T.; Cao, X.; Miao, Y.; Yuan, Y.; Liu, Y.; Ma, F.; Tian, S.; Dai, J.; Ding, Q.; Zheng, H.

doi:10.1101/2022.07.14.499651

bioRxiv · 10.1101/2022.07.14.499651

Vitamin C is an efficient natural product for prevention of SARS-CoV-2 infection by targeting ACE2 in both cell and in vivo mouse models

Zuo, Y.·Zheng, Z.·Huang, Y.·He, J.·Zang, L.·Ren, T.·Cao, X.·Miao, Y.·Yuan, Y.·Liu, Y.·Ma, F.·Tian, S.·Dai, J.·Ding, Q.·Zheng, H.

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Abstract

ACE2 is a major receptor for cell entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2s binding, how to efficiently and flexibly control ACE2 levels for prevention of SARS-CoV-2 infection has not been explored. Here, we revealed Vitamin C (VitC) administration as an effective strategy to prevent SARS-CoV-2 infection. VitC reduced ACE2 protein levels in a dose-dependent manner, while partial reduction of ACE2 can greatly restrict SARS-CoV-2 infection. Further studies uncovered that USP50 is a crucial regulator of ACE2 protein levels, and VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination at Lys788 and degradation of ACE2, without disrupting ACE2 transcriptional expression. Importantly, VitC administration reduced host ACE2 and largely blocked SARS-CoV-2 infection in mice. This study identified an in vivo ACE2 balance controlled by both USP50 and an essential nutrient VitC, and revealed a critical role and application of VitC in daily protection from SARS-CoV-2 infection. HighlightsO_LIVitC reduces ACE2 protein levels in a dose-dependent manner C_LIO_LIVitC and USP50 regulate K48-linked ubiquitination at Lys788 of ACE2 C_LIO_LIVitC blocks the interaction between USP50 and ACE2 C_LIO_LIVitC administration lowers host ACE2 and prevents SARS-CoV-2 infection in vivo C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/499651v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@196682borg.highwire.dtl.DTLVardef@190f14dorg.highwire.dtl.DTLVardef@d22b59org.highwire.dtl.DTLVardef@1c0faa_HPS_FORMAT_FIGEXP M_FIG C_FIG The deubiquitinase USP50 controls ACE2 protein stability and levels, while Vitamin C blocks the USP50-ACE2 interaction and therefore results in ACE2 degradation, offering a flexible and efficient approach to protection of the host from SARS-CoV-2 infection.

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Zuo, Y., Zheng, Z., Huang, Y., He, J., Zang, L., Ren, T., Cao, X., Miao, Y., Yuan, Y., Liu, Y., Ma, F., Tian, S., Dai, J., Ding, Q., Zheng, H.. 2022-07-15. Vitamin C is an efficient natural product for prevention of SARS-CoV-2 infection by targeting ACE2 in both cell and in vivo mouse models. https://doi.org/10.1101/2022.07.14.499651

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