Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion.
Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion.
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DOI：
10.1073/pnas.2012197117
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发表时间：
2020-12-15
影响因子：
11.1
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Zang R;Case JB;Yutuc E;Ma X;Shen S;Gomez Castro MF;Liu Z;Zeng Q;Zhao H;Son J;Rothlauf PW;Kreutzberger AJB;Hou G;Zhang H;Bose S;Wang X;Vahey MD;Mani K;Griffiths WJ;Kirchhausen T;Fremont DH;Guo H;Diwan A;Wang Y;Diamond MS;Whelan SPJ;Ding S
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease-2019 (COVID-19), has swept the world in unprecedented speed. In a few months, SARS-CoV-2 has infected millions of people and caused tens of thousands of deaths. There are no Food and Drug Administration-approved antivirals or vaccines yet available and clinical treatments are limited to supportive therapies that help alleviate the symptoms. Thus, there is an urgent need to identify effective antivirals as countermeasures before safe and effective vaccines are developed, tested, and then produced on a large scale. Our approach is to harness the germline-encoded interferon antiviral response to inhibit SARS-CoV-2 replication thereby limiting its pathogenicity. 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.
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影响因子：
32.4
作者：
Blanc M;Hsieh WY;Robertson KA;Kropp KA;Forster T;Shui G;Lacaze P;Watterson S;Griffiths SJ;Spann NJ;Meljon A;Talbot S;Krishnan K;Covey DF;Wenk MR;Craigon M;Ruzsics Z;Haas J;Angulo A;Griffiths WJ;Glass CK;Wang Y;Ghazal P
通讯作者：
Ghazal P
影响因子：
5.4
作者：
Arias, Carlos F.;Silva-Ayala, Daniela;Lopez, Susana
通讯作者：
Lopez, Susana
影响因子：
30.3
作者：
Case, James Brett;Rothlauf, Paul W.;Whelan, Sean P. J.
通讯作者：
Whelan, Sean P. J.
影响因子：
11.4
作者：
Civra A;Francese R;Gamba P;Testa G;Cagno V;Poli G;Lembo D
通讯作者：
Lembo D
影响因子：
13.5
作者：
Bolen, Christopher R.;Ding, Siyuan;Robek, Michael D.;Kleinstein, Steven H.
通讯作者：
Kleinstein, Steven H.