Several FDA-approved drugs — including for type 2 diabetes, hepatitis C and HIV — significantly reduce the ability of the Delta variant of ’s ’s ability to infect cells by inhibiting protease processing of the spike protein.
“We found that when the cells were pretreated with the selected inhibitors, only MG-101 affected the virus’s entry into cells,” said Narayanan.
In addition, the researchers found that treating cells with a combination of Mpro and PLpro inhibitors had an additive antiviral effect, providing even greater inhibition of SARS-CoV-2 replication.
“In cell culture, we showed that if you combine Mpro and PLpro inhibitors, you have a stronger effect on the virus without increasing toxicity,” said Jose. “This combination inhibition is highly potent.”
To investigate the mechanism by which MG-101 inhibits the activity of Mpro protease, the scientists, including Manju Narwal, postdoctoral scholar in biochemistry and molecular biology, used X-ray crystallography to obtain a high-resolution structure of MG-101 in complex with Mpro.
“We were able to see how MG-101 was interacting with the active site of Mpro,” said Narwal. “This inhibitor mimics the polyprotein and binds in a similar manner to the protease, thereby blocking the protease from binding to and cutting the polyprotein, which is an essential step in the virus’s replication.”
Murakami added, “By understanding how the MG-101 compound binds to the active site, we can design new compounds that may be even more effective.”
Indeed, the team is in the process of designing new compounds based on the structures they determined by X-ray crystallography. They also plan to test the combination drugs that they already demonstrated to be effective in vitro in mice.
Although the scientists studied the Delta variant of SARS-CoV-2, they said the drugs will likely be effective against Omicron and future variants because they target parts of the virus that are unlikely to mutate significantly.
“The development of broad-spectrum antiviral drugs against a wide range of coronaviruses is the ultimate treatment strategy for circulating and emerging coronavirus infections,” said Jose. “Our research shows that repurposing certain FDA-approved drugs that demonstrate effectiveness at inhibiting the activities of Mpro and PLpro may be a useful strategy in the fight against SARS-CoV-2.”
Reference: “Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay” by Anoop Narayanan, Manju Narwal, Sydney A. Majowicz, Carmine Varricchio, Shay A. Toner, Carlo Ballatore, Andrea Brancale, Katsuhiko S. Murakami and Joyce Jose, 25 February 2022, Communications Biology.
DOI: 10.1038/s42003-022-03090-9
Other authors on the paper include Sydney A. Majowicz, graduate student, and Shay A. Toner, undergraduate student, Penn State; Carmine Varricchio, postdoctoral research associate, and Andrea Brancale, professor of medicinal chemistry, Cardiff University; and Carlo Ballatore, professor of medicinal chemistry, University of California, San Diego.
The National Institutes of Health, Welsh Government Office for Science and Huck Institutes of the Life Sciences at Penn State (COVID-19 Seed Grant for Jose Laboratory) supported this research.