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Cholesterol-25-Hydroxylase Inhibits Sars-Cov-2 And Other Viral Infection Mechanisms

The new coronavirus SARS-CoV-2 causes the 2019 Coronavirus Disease (COVID-19) and is now raging around the world. There is currently no US Food and Drug Administration (FDA) approved method for the treatment of COVID-19. Although several therapies are undergoing clinical trials, the current standard treatment methods are mainly to provide patients with convalescent serum and anti-fever drugs. In order to speed up the search for new COVID-19 treatments, scientists are testing reusable drugs (that is, drugs that have been safely used in the human body so that they can be quickly applied to the clinic) to reduce the ability of this virus infection.

In a new study, researchers from the University of California, San Diego School of Medicine found that Cholesterol-25-hydroxylase (CH25H) can prevent the entry of  the coronavirus SARS-CoV-2 by removing cholesterol from the cell membrane.

According to existing research, it is known that the coronavirus will induce interferon (IFN) after infection. Interferon is an active protein (mainly glycoprotein) produced by monocytes and lymphocytes with multiple functions. They have broad-spectrum antiviral activities on the same cells, affecting cell growth, differentiation, and regulating immune function. After detecting the molecular pattern associated with viral infection, the IFN pathway is activated, prompting the further activation of hundreds of interferon-stimulating genes (ISG), thereby interfering with the virus life cycle process. Human type I interferons including IFN-α and IFN-β work through the ubiquitously expressed type I interferon receptor (IFNAR), while type III interferon IFN-λ and epithelial restricted type III interferon receptor Combine and function. In vitro and clinical studies have shown that SARS-CoV-2 is sensitive to type I IFN, and type I IFN treatment may be a promising treatment strategy for COVID-19.

Figure 1. 25-Hydroxycholesterol, produced by the interferon‐stimulated protein CH25H, inhibits the entry of SARS-CoV-2, SARS-CoV, and MERS-CoV.

Cholesterol 25-hydroxylase (CH25H) is a gene that encodes the enzyme that synthesizes hydroxysterol 25-hydroxycholesterol (25HC) from cholesterol. CH25H is an interferon-inducible gene that is strongly upregulated in SARS-CoV-2 infected lung epithelial cell lines and COVID-19 infected patients. Clinical studies have found that 25HC, the product of interferon-induced enzyme CH25H, has broad-spectrum antiviral activity against human coronaviruses. Previous studies have shown that 25HC can inhibit a variety of viruses from entering cells, including VSV, HIV, NiV, EBOV and ZIKV. However, the mechanism by which 25HC regulates virus entry is unclear. Existing studies have shown that the endoplasmic reticulum localization enzyme ACAT uses fatty acyl-coenzyme a and cholesterol as substrates to produce cholesterol esters, which are stored in cytoplasmic lipid droplets and induce the consumption of accessible cholesterol of plasma membrane through an unknown mechanism. When exploring the mechanism of 25HC function, the researchers found that 25HC triggers the consumption of accessible cholesterol in the plasma membrane by activating acyl coa:cholesterol acyltransferase (ACAT), thereby inhibiting the entry of viruses. Cholesterol has multiple effects on the lipid bilayer. The increase or decrease of cholesterol may be accompanied by changes in membrane fluidity, polarity, thickness, and inherent curvature. In addition, the change of cholesterol can affect the function of the entire membrane protein (including viral receptors or co-receptors) by changing its conformation or distribution on the plasma membrane. These changes will directly or indirectly affect the fusion of the virus and the cell membrane, and cell membrane fusion is critical to the release of the viral genome. Due to the importance of membrane cholesterol in virus-cell fusion, the mechanism of 25HC may extend to the cell membrane fusion process of other viruses.



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Cholesterol-25-Hydroxylase Inhibits Sars-Cov-2 And Other Viral Infection Mechanisms

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