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GSK-3 inhibitors are promising for the treatment of coronavirus infections

Researchers in the United States are proposing new approaches to treating infectious diseases Coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – Drugs that cause coronavirus disease 2019 (COVID-19).

This study showed that inhibition of phosphorylation of important structural proteins expressed in coronavirus impaired SARS-CoV-2 infection in human lung epithelial cells.

The team used an inhibitor of the host cell protein glycose-glycen synthase kinase 3 (GSK-3) to block the phosphorylation of the SARS-CoV-2 nucleocapsid protein, which is essential for coronavirus replication.

Researchers have also demonstrated that the GSK-3 inhibitor lithium is associated with a significant reduction in the risk of COVID-19.

“Therefore, targeting GSK-3 may provide antiviral therapy for COVID-19 and possible future coronavirus infections,” said Peter Klein and colleagues at the University of Pennsylvania. I will.

The preprinted version of the research treatise is medRxiv* Servers and articles have been peer reviewed.

Coronavirus outbreaks may occur in the future

Klein et al. Warn that, given the massive coronavirus outbreaks that have occurred in the last two decades, they are more likely to occur in the future.

“In addition to the development of effective vaccines, antiviral strategies targeting conserved mechanisms of coronavirus replication and infection may be needed for COVID-19 and potential future outbreaks of coronavirus. There are, “they say.

What is already known about the nucleocapsid protein?

The nucleocapsid (N) protein is essential for coronavirus replication, transcription, and assembly.

However, the N protein expressed by the SARS-CoV-1 virus (which caused the development of SARS from 2002 to 2004) requires phosphorylation by the host cell GSK-3 in the arginine-serine (RS) domain. ..

In addition, the GSK-3 inhibitor lithium, a common treatment for bipolar disorder, inhibits the replication of various coronaviruses, including SARS-CoV-1, porcine epidemic diarrhea virus, and transmissible gastroenteritis virus. ..

“Interfering with the conserved dependence of the N protein on the host protein GSK-3 may be a viable approach for treating COVID-19 and potential future outbreaks of coronavirus.” Klein and the team wrote.

Studies have shown that the SARS-CoV-1 N-protein shares only 20-30% sequence identity with many other coronavirus N-proteins, whereas all viruses are N-terminal and C-terminal. It has an RS domain in between. Saved domain.

The RS domain of the SARS-CoV-1 N protein contains a repetitive motif (SXXXS) that is often associated with GSK-3 phosphorylation.

In addition, one study recently discovered that the SARS-CoV-2N protein is highly phosphorylated within the RS domain. However, previous studies have not tested whether GSK-3 phosphorylates the SARS-CoV-2 N protein or whether lithium exerts an antiviral effect on SARS-CoV-2. Hmm.

What did the researchers do?

Currently, Klein et al. Have found that the RS domain of the SARS-CoV-2 N protein is 90% similar to the RS domain of the SARS-CoV-1 N protein, each containing two sets of three SXXXS motifs. Shown.

Although the N protein sequences of other coronaviruses are divergent, the team also showed that they still carry the SXXXS motif.

“GSK-3 consensus sites have been found in the N proteins of various coronaviruses, making GSK-3 inhibitors effective antiviral therapies for other coronavirus infections, including those that may occur in the future. It could be, “says the researchers.

Next, Klein et al. Tested the effects of various GSK-3 inhibitors on the SARS-CoV-2N protein expressed in human fetal kidney 293T cells.

They found that lithium chloride and several other small molecule GSK-3 inhibitors, including CHIR99021, AR-A014418, and enzastaurin, all inhibit N phosphorylation, making GSK-3 essential for N. I strongly supported that. Protein phosphorylation..

In addition, the team found that the GSK-3 inhibitor CHIR99021 also impaired SARS-CoV-2 replication in the human lung epithelial cell line Calu-3...

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GSK-3 inhibitors block the replication of SARS-CoV2-infected cells: A. Dose-response analysis of Calu-3 cells treated with the GSK-3 inhibitor CHIR99021 or enzastaurin (UPenn). Cells were treated with the indicated concentrations of drug and then inoculated with SARS-CoV-2. Cells were fixed at 48 hpi and the total number of cells detected by immunofluorescence of dsRNA (green) and virus infection rate (blue) were evaluated. B. Calu-3 cells were treated with vehicle or the indicated concentration of CHIR99021, inoculated with SARS-CoV-2, fixed at 48 hpi, and peplomer detected by immunofluorescence (UCLA). Enzastaurin did not affect the viral infection of Calu-3 cells.

GSK-3 inhibitors block the replication of SARS-CoV2-infected cells: A. Dose-response analysis of Calu-3 cells treated with the GSK-3 inhibitor CHIR99021 or enzastaurin (UPenn). Cells were treated with the indicated concentrations of drug and then inoculated with SARS-CoV-2. Cells were fixed at 48 hpi and the total number of cells detected by immunofluorescence of dsRNA (green) and virus infection rate (blue) were evaluated. B. Calu-3 cells were treated with vehicle or CHIR99021 at the indicated concentration, inoculated with SARS-CoV-2, fixed at 48 hpi and fixed. Spike protein Detected by immunofluorescence (UCLA). Enzastaurin did not affect the viral infection of Calu-3 cells.

Testing whether lithium reduces the risk of COVID-19

Because lithium is already widely used in the treatment of bipolar disorder, researchers investigated whether patients taking lithium had a lower risk of developing COVID-19 compared to the general population. ..

They conducted a retrospective analysis of data from three major US healthcare systems.

The researchers included data from 121,589 people from the University of Pennsylvania Health System (UPHS), 115,073 from the Mount Sinai Medical Center (MSMC), and 102,420 from the University of Iowa Hospital and Clinic (UIHC). As of February 2021, all patients had been tested for SARS-CoV-2 by the polymerase chain reaction (PCR).

Of these individuals, 8,856 (7.2%) UPHS patients, 10,597 (9.2%) MSMC patients, and 16,170 (15.8%) UIHC patients were confirmed to be SARS-CoV-2 positive. ..

In all three healthcare systems, 7% of patients taking lithium developed COVID-19, compared with 15% in the general population.

In addition, a meta-analysis of data using a random effects model showed that patients taking lithium were 49% less likely to develop COVID-19 than patients not taking lithium.

What did the author conclude?

The team proposes that inhibition of N protein phosphorylation underlies the antiviral activity of lithium and other GSK-3 inhibitors against SARS-CoV-2.

“Developing a GSK-3 inhibitor that safely and effectively inhibits N-phosphorylation has promising potential for controlling SARS-CoV-2 and other possible future coronavirus infections. It’s an approach, “says Klein et al.

Researchers also point out that this approach is based on a well-defined mechanism and utilizes a clinically tested, well-tolerated drug that can be rapidly reused for COVID-19.

*Important Notices

medRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.

GSK-3 inhibitors are promising for the treatment of coronavirus infections

Source link GSK-3 inhibitors are promising for the treatment of coronavirus infections

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