The cholesterol metabolite 27-hydroxycholesterol inhibits SARS-CoV-2 and is markedly decreased in COVID-19 patients

Abstract

There is an urgent need to identify antivirals against the coronavirus SARS-CoV-2 in the current COVID-19 pandemic and to contain future similar emergencies early on. Specific side-chain cholesterol oxidation products of the oxysterols family have been shown to inhibit a large variety of both enveloped and non-enveloped human viral pathogens. Here we report on the in vitro inhibitory activity of the redox active oxysterol 27-hydroxycholesterol against SARS-CoV-2 and against one of the common cold agents HCoV-OC43 human coronavirus without significant cytotoxicity. Interestingly, physiological serum levels of 27-hydroxycholesterol in SARS-CoV-2 positive subjects were significantly decreased compared to the matched control group, reaching a marked 50% reduction in severe COVID-19 cases. Moreover, no correlation at all was observed between 24-hydroxycholesterol and 25-hydroxycholesterol serum levels and the severity of the disease. Opposite to that of 27-hydroxycholesterol was the behaviour of two recognized markers of redox imbalance, i.e. 7-ketocholesterol and 7β-hydroxycholesterol, whose serum levels were significantly increased especially in severe COVID-19. The exogenous administration of 27-hydroxycholesterol may represent in the near future a valid antiviral strategy in the worsening of diseases caused by present and emerging coronaviruses.

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

“…It is intriguing to speculate that oxysterols or direct SCAP inhibitors, such as fatostatin ( Kamisuki et al., 2009 ) or its derivatives, could have antiviral properties. Consistent with this possibility, one study showed that 27-hydroxycholesterol (27OHC) exerted SARS-CoV-2 antiviral activity in VeroE6 cells at 10 μM, and that overall oxysterols were lower in patients with moderate and severe COVID-19 symptoms than in controls ( Marcello et al., 2020 ). Another study showed that 25OHC had potent SARS-CoV-2 antiviral activity at similar concentrations ( Zang et al., 2020 ).…”

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…Furthermore, 25HC inhibited SARS-CoV-2 infection in lung epithelial cells and reduced viral entry in human lung organoids, presumably by preventing viral membrane fusion through activation of the ER-localized acyl-CoA:cholesterol acyltransferase, which leads to the depletion of cholesterol from the plasma membrane ( S. Wang et al, 2020 ). Similar to 25HC, another cholesterol oxidation metabolite, 27-hydroxycholesterol, was shown to inhibit SARS-CoV-2 infection in Vero-E6 cells with an EC 50 of 1.4 μM ( Marcello et al, 2020 ). Interestingly, serum levels of 27-hydroxycholesterol were significantly decreased (50%) in SARS-CoV-2 infected patients, compared to the control group.…”

Combined in silico and in vitro approaches identified the antipsychotic drug lurasidone and the antiviral drug elbasvir as SARS-CoV2 and HCoV-OC43 inhibitors

“…In order to evaluate the anti-HCoV-OC43 activity of the selected compounds, focus reduction assays were performed on MRC-5 cells, as described in the Materials and Methods section and elsewhere ( Marcello et al, 2020 ). Results on antiviral activity and cell toxicity are reported in Table 3 , Figure 4 and Fig.…”

“…Human coronavirus strain OC43 (HCoV–OC43) (ATCC® VR-1558) was purchased from ATCC (American Type Culture Collection, Rockville, MD, USA). The virus was propagated in MRC-5 cells at 33°C, in a humidified 5% CO 2 incubator, and titrated by standard plaque method on MRC-5 cells, as described elsewhere ( Marcello et al, 2020 ); titers were expressed in terms of plaque forming units per ml (PFU/ml).…”