Many FDA-approved drugs – including type 2 diabetes, hepatitis C and HIV – reduce the ability of Delta variants of SARS-CoV-2 to copy in human cells, according to a new research led by scientists in Penn State. In particular, the team found that these drugs inhibit certain imaging enzymes, called proteases, which are essential for the copy of SARS-CoV-2 in infected human cells.
Joyce Jose, assistant professor of biology and genetics, Penn State said “SARS-CoV-2 drugs are targeted for increased protein, but this protein is under intense pressure and, as we have seen with Omicron, could face major mutations. ” . “There is also an urgent need for SARS-CoV-2 paramedics who are attacking the immune system in addition to non-viable proteins.”
Previous research has shown that two SARS-CoV-2-proteases enzymes including Mpro and PLpro-promising anti-inflammatory drugs. Pfizer’s COVID-19 therapy Paxlovid, for example, attacks Mpro. According to Jose, these enzymes are relatively stable; therefore, they are less likely to develop drug-resistant mutations quickly.
Katsuhiko Murakami, a professor of biology and genetics, Penn State, notes that these viruses are immune, because their ability to break down, or cut, proteins, is important for the copy of SARS-CoV-2 in viruses .
“SARS-CoV-2 produces long-lasting proteins, called polyproteins, from its RNA molecules that must be synthesized into a single protein by these regulatory elements. which causes the formation of enzymes of bacteria and proteins to start the virus as soon as it enters the cell., ”Murakami explained. “If you prevent one of these viruses, the spread of SARS-CoV-2 in the virus can be stopped.”
The results were published today (February 25th) in the press Communication Biology.
The team compiled statistics to identify inhibitors of Mpro and PLpro proteases in human cells.
“Although there are some experiments, we have designed our own new story so it can be carried out in living cells, which allows us to measure the amount of toxins in the human body,” Jose said. .
The researchers used their study to test a library of 64 compounds — including antiretrovirals and hepatitis C; cysteine proteases, which occur in some protozoan viruses; and dipeptidyl peptidase, a human enzyme in type 2 diabetes for their ability to inhibit Mpro or PLpro. Of the 64 compounds, the team identified eleven related to Mpro projects and five related to PLpro projects in terms of a 50% reduction in. vaccine works with 90% cellular capacity.
Anoop Narayanan, a professor of biological and molecular biology, monitors the activity of compounds using live microscopy.
“We designed the test so that if the group were affected by proteases, you would see light in other parts of the cell,” Narayanan said.
Subsequently, the team evaluated the antiviral activity of 16 PLpro and Mpro inhibitors on SARS-CoV-2 strains in life. human cells in a study of BSL-3, by Eva J. Pell ABSL-3 Laboratory for Advanced Bioological Research in Penn State, and found that eight of them had cancer vaccine and SARS-CoV-2. In particular, they found that Sitagliptin and Daclatasvir inhibited PLpro, and MG-101, Lycorine HCl and Nelfinavir mesylate inhibited Mpro. Of these, the team found that MG-101 also prevented the virus from infecting the virus by inhibiting the control of the virus. increase protein.
“We found that when the cells were already vaccinated with selective inhibitors, MG-101 only affected the entry of the virus,” Narayanan said.
In addition, the researchers found that doing treatment Cells in combination with Mpro and PLpro inhibitors have additional antiviral effects, providing greater inhibition of SARS-CoV-2 replication.
“In cell culture, we have shown that if you combine Mpro and PLpro inhibitors, you have a strong effect on the virus without increasing toxicity,” says Jose. “This connection is very strong.”
To investigate the mechanism by which MG-101 inhibits the activity of Mpro protease, scientists, including Manju Narwal, a biologist and anthropologist. biology of biologyX-ray crystallography was used to obtain a high resolution of MG-101 in complex with Mpro.
“We were able to see how the MG-101 interacts with the Mpro website,” Narwal said. “This inhibitor mimics polyprotein and binds in a similar way to protease, thus blocking protease from binding to and cutting polyprotein, which is an important step in the cell cycle.”
Murakami added, “By understanding how the MG-101 complex integrates with the workplace, we can design new compounds that can be highly effective.”
Of course, the team is in the process of designing new compounds based on systems determined by X-ray crystals. They also planned to test co-drugs that had already been shown to be effective in vitro in mice.
Although scientists have studied Delta variants of SARS-CoV-2, they say the drugs are likely to have an effect on Omicron and subsequent variants because they lead to parts of the virus that are less likely to change. .
“Improving multidrug resistance against coronaviruses is the best treatment strategy for the spread and emergence of coronavirus infections,” Jose said. “Our research suggests that the recovery of some FDA-approved drugs that appear to be effective in inhibiting Mpro and PLpro activities may be a useful strategy in the fight against SARS-CoV-2.”
Other authors on the paper include Sydney A. Majowicz, graduate student, and Shay A. Toner, graduate student, Penn State; Carmine Varricchio, postdoctoral research consultant, and Andrea Brancale, professor of medicine, Cardiff University; and Carlo Ballatore, professor of medicine, University of California, San Diego.
Communication Biology, DOI: 10.1038 / s42003-022-03090-9
Pennsylvania State University
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