With each new infection, the pandemic coronavirus gets a new chance to mutate and adapt, creating opportunities for the virus to evolve new variants that evade the immune system and make us sicker. Masu.
Antiviral drugs such as paxlobid and remdesivir aim to stop this constant evolution in individual patients, shorten the disease, erase the opportunity for mutation, and reduce infections. But one antiviral drug appears to be backfiring, increasing the chances that SARS-CoV-2 will mutate.
according to New study peer-reviewed in Naturean antiviral drug called molnupiravir, has been linked to a specific SARS-CoV-2 mutational signature that happened to occur in 2022, the year the drug was introduced.
The study’s authors, led by researchers from London’s Francis Crick Institute and the University of Cambridge, scanned more than 15 million SARS-CoV-2 genome sequences found in global databases. They extracted unique mutational signatures that were closely related to those found in viruses from patients known to have been treated with molnupiravir. These signs of suspected molnupiravir-related mutations were also consistent with those seen in viruses tested in clinical trials of molnupiravir. Overall, the signs appeared in older people, who are most likely to be treated with antiviral drugs, and in countries where molnupiravir is frequently used.
The researchers not only found molnupiravir-related mutations, but also characterized them. The researchers found evidence that some of the molnupiravir-related mutations are undergoing positive selection, meaning they are increasing in frequency, suggesting that they are somehow advantageous to the virus. They also noted that some viruses with mutations associated with molnupiravir formed clusters and were transmitted from person to person, suggesting that these drug-induced mutations lead to subsequent transmission.
The results show that “molnupiravir induces new mutations and increases the genetic diversity of surviving virus populations,” lead author and postdoctoral researcher Theo Sanderson of the Francis Crick Institute said in a statement. said in a statement.
So far, there is no evidence that molnupiravir contributed to the development of the most important SARS-CoV-2 variants, such as Omicron. And the clusters of infections seen in the data are small. Still, Professor Sanderson said the study results were important in weighing the risks and benefits of molnupiravir and highlighted the “potential for mutations with persistent antivirals”.
code switching
Molnupiravir appears to induce these mutational signatures in a unique way compared to some other antivirals. This small molecule drug is a nucleoside analog. That is, it serves as a building block for RNA, especially cytosine (represented by C in RNA and G, A, C, and U/T, respectively, in the DNA code).
During infection, SARS-CoV-2, a virus with a positive-sense single-stranded RNA genome, copies its genome inside human cells in order to package it into a new virus that infects more cells. must be created. Replicates using a special enzyme called RNA-dependent RNA polymerase. In the presence of molnupiravir, the polymerase may jump to a new copy of the RNA strand in place of the cytosine in the active form of molnupiravir. In other words, C switches to M. The idea is that if there are enough M to replace Cs, a new copy will be generated. RNA molecules are full of errors, so their creation leads to an “error catastrophe.” Essentially, this is the concept that the genetic error rate exceeds a threshold for viral survival.
But apparently, having an M in the code is not necessarily fatal, and the virus will continue to replicate. Then things get even worse. Once incorporated into an RNA strand, M can transition (tautomerize) to another form that resembles another RNA component, uracil or U.
So, between normal RNA strands, a C pairs with a G opposite a guanine, and a U pairs with an A opposite an adenine. However, when non-catastrophic molnupiravir is present, the first pair of G pairs with M. It can then pretend to be U and pair up with A in the next replication cycle. The result is a mutation where G is replaced by A in the code. Then, as the number of copies increases, the C can switch to a U (or T in the DNA code). Although other letter-switching confusions may occur, the unusually high frequency of G-to-A and C-to-U switches was a common mutational signature associated with molnupiravir.
big risk
Molnupiravir is unique in this respect. Remdesivir is also a nucleoside analog, but it is thought to cause “chain termination,” which stops new strands of RNA from growing. Paxrobid, on the other hand, works to stop viruses by targeting enzymes needed for replication.
when Molnupiravir approved in the US, there were concerns about its potential to cause mutations in people’s DNA rather than the virus. For this reason, Not recommended for use by pregnant people. But new data has raised further concerns about the mutation. And with this risk comes lackluster efficacy data. In the Food and Drug Administration’s final data analysis, Merck & Co., the manufacturer of molnupiravir, estimated that the drug was only 30 percent effective at preventing hospitalization and death, combining data from two sets of trials.
FDA advisers summarized the data at the time as “not overwhelmingly positive” and “modest at best.” They voted by a narrow margin of 13 to 10 in favor of approving the drug. The drug never took hold in Europe. Earlier this year, the European Medicines Agency refused to issue marketing authorization for molnupiravir. Following the EMA’s rejection, Merck said it was confident in the drug’s role in the fight against COVID-19 and would appeal the decision. Molnupraivir is approved for use in more than 20 countries, including the United States, Australia, China, Japan and the United Kingdom, but its use has been curtailed in many countries.
Overall, the authors of the new study say their findings should be considered in decisions regarding continued and subsequent use of molnupiravir. “These data will help us continue to evaluate the risks and benefits of this treatment and inform the future development of mutagens as antivirals, especially against viruses with high mutational resistance such as coronaviruses. The researchers concluded that
