Several drugs approved by the US regulator, the Food and Drug Administration (FDA), including for type 2 diabetes, hepatitis C and HIV, significantly reduce the ability of the delta variant of Sars-CoV-2 to spread in the human body. A team led by scientists from Penn State University found that these drugs inhibit viral enzymes called proteases, which are essential for the replication of the coronavirus in cells.
“Vaccines against Sars-CoV-2 target the spike, but this protein is under high selection pressure and, as we have seen with omicron, can undergo significant mutations. There remains an urgent need for therapeutic agents that target parts of the virus, in addition to the spike protein, that are not as likely to evolve,” says Joyce Jose, assistant professor of biochemistry and molecular biology at Penn State and one of the study’s authors. , published in the journal Communications Biology.
Previous research has shown that two Sars-CoV-2 proteases – Mpro and Plpro – are promising targets for the development of antivirals. According to Joyce José, these enzymes are relatively stable. Therefore, they are unlikely to rapidly develop drug-resistant mutations. Pfizer’s Covid-19 drug Paxlovid, for example, targets Mpro.
Katsuhiko Murakami, professor of biochemistry and molecular biology at Penn State, explains that due to their ability to cleave or cut proteins, proteases are essential for the replication of Sars-CoV-2 in infected cells. “The coronavirus produces long proteins from its RNA genome, the polyproteins, which, in an orderly fashion, must be cleaved into individual proteins by these proteases, leading to the formation of functional enzymes and viral proteins to initiate replication of the virus as soon as it enters the cell, “he explains. “If you inhibit one of these proteases, the spread of Sars-CoV-2 in the infected person can be stopped.
In search of this effect, the team designed a test to rapidly identify the protease inhibitors Mpro and PLpro in living human cells, which allowed them to also assess the toxicity of possible inhibitors. To do this, they tested a library of 64 compounds – including inhibitors of HIV and hepatitis C proteases, cysteine proteases, found in some protozoan parasites, and dipeptidyl peptidase, a human enzyme implicated in diabetes. type 2 – for their ability to inhibit Mpro or PLpro.
Of the 64 compounds, the team identified 11 that affected Mpro activity and five that affected Plpro activity, based on a threshold of 50% reduction in protease activity with viability 90% cell. Next, the antiviral activity of these 16 inhibitors against Sars-CoV-2 in living human cells was evaluated. “We found that when cells were pretreated with the selected inhibitors, only MG-101 affected virus entry into cells,” says Anoop Narayanan, research associate professor of biochemistry and molecular biology at the American University.
By further investigating the mechanism by which MG-101 inhibits Mpro activity, scientists found that this inhibitor mimics polyprotein and similarly binds to protease, thereby blocking its binding. “By understanding how MG-101 binds to the active site, we can design new compounds that may be even more effective,” says Murakami. Now the team is designing new compounds based on the discovered structures. They also plan to test combination drugs that have already been shown to be effective in in vitro tests and in mice.
Although the scientists have studied the delta variant, they point out that the drugs are likely to be effective against omicron and future strains 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 infections by this virus”, stresses Joyce José. “Our research shows that retargeting certain FDA-approved drugs that demonstrate efficacy in inhibiting the activities of Mpro and PLpro could be a useful strategy in the fight against Sars-CoV-2.
decrease in efficiency
A study published in The Lancet Respiratory Medicine by Providence, one of the largest health systems in the United States, confirms the overall effectiveness of vaccines in preventing serious infections resulting from hospitalization for Covid-19, but shows also a substantial drop in protection after six years. month. month. Carried out by a team of doctors and scientists from the Providence Research Network, the research looked at data from nearly 50,000 hospital admissions between April and November 2021, finding that vaccines were 94% effective in preventing hospitalization. 50 to 100 days after injection, but efficacy dropped to 80.4% between 200 and 250 days later, with even more rapid declines beyond this period.