Bad news for Paxlovid?Coronavirus can find multiple ways to avoid COVID-19 medicines | Chemistry

Prescriptions for Pfizer’s blockbuster Paxrovid have skyrocketed in recent weeks. This is good news for many COVID-19 patients, as pills have been shown to reduce the serious illness caused by SARS-CoV-2 infection. However, studies in many new laboratories have shown that coronavirus can mutate in ways that make it less susceptible to the drug. It is the most widely used of the two oral antivirals licensed to treat COVID-19 in the United States. Researchers have discovered some of these mutations in variants that are already circulating in infected people, and doctors could quickly lose one of the best treatments to fight COVID-19. It raises new concerns that there is.

In summary, studies show that “when you put pressure on the virus, the virus escapes,” said David Ho, a virologist at Columbia University who first recorded a drug-resistant mutation in HIV about 30 years ago. Ho was not involved in the new study, but he is doing similar work on SARS-CoV-2. The newly identified mutations have not yet spread, but Ho and many other scientists consider it a matter of time. “Given the amount of infection there, it will come,” says Ho.

Tolerance studies follow other recent concerns about Paxrovid. Paxrovid remains restricted in the United States to people with risk factors who are more likely to develop severe COVID-19. Checking case reports widely reported by the media, some studies have shown that only a small proportion of infected individuals who take the usual 5-day course feel better at first and only recover from their symptoms. understood.And there are increasing questions about whether Paxlovid helps people who are not at high risk of serious illness — Pfizer earlier this month. Discontinued large-scale drug trials Patients with standard-risk COVID-19 failed to show statistically significant protection against death or hospitalization.

The US Food and Drug Administration (FDA) granted an emergency use authorization for Paxlovid in December 2021. The drug is composed of the active antiviral drug nirmatorelvir and ritonavir, a compound that slows the breakdown of nirmatorelvir in the body. Paxlovid was slow to deploy due to a bottleneck in the production of Nirmatrelville. US doctors issued less than 40,000 prescriptions a week until mid-April. Since then, prescriptions have skyrocketed to more than 160,000 people a week, according to the latest figures from the Centers for Disease Control and Prevention.

The rise creates selective pressure in the virus and supports mutations that help the virus survive in the presence of the drug. Also, as each infected person makes trillions of copies of SARS-CoV-2, the virus has many opportunities to test for different mutations as it replicates.

So far, these mutations do not seem to interfere with the effectiveness of Paxlovid. Nirmatorelvir is the main protease of SARS-CoV-2 (M)^ProfessionalAn important step in reproduction of SARS-CoV-2, as it cleaves long precursor molecules produced by the virus into shorter active proteins. In February, Pfizer researchers JBC Accelerated Communication that Nirmatrelville continued to be effective in stopping M’s activity^Professional Multiple SARS-CoV-2 variants such as alpha, beta, delta, gamma, lambda, omicron, and the original strain.

However, recent studies suggest that the virus is ready to develop resistance. This is the fate of many antiviral drugs. For example, two preprints posted on bioRxiv on June 7 show that lab-grown SARS-coV-2 quickly gains the ability to evade the attack on Nirmatrelville. Two research groups independently cultivated coronavirus in low-level Nirmatrelvir, killing some, but not all, of the virus. Such tests are intended to simulate what happens in infected individuals who are not taking the entire drug regimen or in immunocompromised patients who have problems removing the virus.

One of these studies, led by Belgian KU Leuven virologist Dirk Jochmans, was after 12 rounds of Nilmatrelvir treatment. SARS-CoV-2 accumulated 3 mutations-Positions of 50, 166, and 167 of the series of amino acids that make up M^Professional– This reduced the virus’s susceptibility to nirmatorelvir by a factor of 20, as determined by the dose of drug required to kill half of the virus in the sample. Another study, led by Judith Margaret Gottwayne, an immunologist at the University of Copenhagen, We also discovered mutations that give potential resistance. At M positions 50 and 166^Professional .. When those mutations occurred together, the virus was 80-fold less susceptible to nilmatrelvir. “This tells us the mutation we should be looking for [in patients]”Gottwayne says.

Indeed, some of these mutations are already found in people infected with the coronavirus, according to a study by Adam Godzik, a bioinformatics expert at the University of California, Riverside. Godzik and his colleagues scrutinize the GISAID database, a catalog of over 10 million SARS-CoV-2 genomes sequenced from viruses isolated from infected individuals, and search for amino acid changes at the M position. Did.^Professional Near where the nirmatrelvir joins. In a bioRxiv preprint posted on May 30, they reported mutations to amino acids 166 and 167, two resistance mutations flagged by the Belgian group.Already infected with a virus that is prevalent in people.. Godzik said these mutations were likely to occur randomly because they occurred before Paxlovid was widely used. However, he revealed that the enzyme has some flexibility in these positions, adding that the virus can help evade the drug.

And the list of potential resistance mutations continues to grow.In a paper submitted to bioRxiv yesterday, Jun Wang, a medicinal chemist at Rutgers University, and his colleagues Report 66 common mutations To M^Professional Near the Nirmatorelvir binding site. Like Godzik’s team, they scanned the GISAID database to find modified versions of proteases, but they’re one step further. Add genes to each of these variants of M^Professional To E. coli Bacteria, they created an enzyme supply for additional testing: first determine if each mutant still fulfilled its essential obligation to cleave the viral protein, then the mutation M. Decided whether to enable^Professional Resist Nirmatrelville. Of the 66 mutants, 11 retain the function of the protease (the others impair it), and 5 of the 11 are resistant to nirmatorelvir, at least 10 times the drug to kill half of the virus in the sample. I needed to increase it. One of these variants had the resistance mutations previously seen at positions 166, while the other four had new workarounds at positions 144, 165, 172, and 192. I did. The time it takes for resistance to appear. “

So why isn’t that happening already? One possibility is that enough people have not yet taken Paxlovid to mutate the virus.Another explanation is that it can take multiple mutations in M, says the king.^Professional Makes the virus fully functional and easy to infect while evading Paxlovid. So far, Mayo Clinic infectious disease specialist Aditya Shah has found that patients with symptom rebound occur in less than 2% of people taking medication, but rebound is the cause. It doesn’t seem to be. Resistance mutation. “It’s encouraging,” says Shah, but it doesn’t prove that the virus won’t eventually get around the drug.

Pfizer states that the Pax-Rovid regimen may prevent resistance. Patients take the drug only for a short period of time and usually get a dose “many times higher” than is needed to prevent the virus from replicating inside the cell, thereby minimizing the chance of the virus mutating. Says Kit Longley, a company spokesman.

Administering multiple antiviral drugs to a patient can prevent resistance by making it difficult for the virus to bypass different compounds at the same time. This is a strategy that has proven to be very effective in treating other viruses such as HIV and hepatitis C. The other two SARS-CoV-2 antivirals are licensed in the United States, but they have drawbacks. Another oral drug, molnupiravir, has proven to be significantly less effective than Paxlovid and induces random genetic mutations in the virus, raising safety concerns. It can also create dangerous new variants, Some scientists warn. Also, remdesivir, which interferes with the virus’s ability to copy the genome, is only allowed in inpatients and should be given intravenously.The preprint posted on bioRxiv yesterday More effective when combined with Molnupiravir and Nirmatorelville At least in mice, in the fight against SARS-CoV-2 infections than antiviral drugs administered alone. However, this strategy has not yet been widely accepted by physicians.

Meanwhile, pharmaceutical companies are competing to complete clinical trials of additional SARS-CoV-2 antivirals, some targeting M.^Professional On various sites. But they are not yet available.And many researchers, including representatives of the neglected diseases nonprofit initiative, Pfizer Not making Paxlovid readily available for combination therapy trials.. Some are skeptical, but the company says it plans to do those studies themselves.

Paxlovid remains essentially alone until more antivirals are available, raising the fear that sooner or later it will lose its punch. When pushed by a single antiviral drug, the virus usually finds a way around the drug, says Gottwayne. “If it can happen, it will happen.” And, at least according to the latest lab results, it can happen.