Some SARS-CoV-2 variants showing signs of becoming resistant to Paxlovid

A new study suggests paxlovid should be reserved for the highest risk patients because some mutations are already showing signs of evolving into resistant forms. The genetic study of SARS-CoV-2 variants found that some pre-existing SARS-CoV-2 strains, including Delta and Omicron, could resist the drug. Findings appeared in a preprint on bioRxiv and have not yet been formally peer-reviewed. A target on the virus for drug therapy is the main protease (Mpro), a cysteine protease. In a virus, proteases are involved in viral replication and an active ingredient in Paxlovid, nirmatrelvir, inhibits Mpro activity stopping viral replication. Using the Global Initiative on Sharing Avian Influenza Data (GISAID) database, the researchers analyzed various SARS-CoV-2 sequences where they found mutations of 66 Mpro mutations located at the binding site used by nirmatrelvir. They then took a closer look at the Mpro mutations for their enzymatic activity, and how well they responded to the drug. “It is important for the mutant virus to maintain the fitness of replication and transmission as the wild-type virus to become dominant,” said the study’s lead author, Jun Wang, PhD, associate professor at the Rutgers Ernest Mario School of Pharmacy, in a note to Pharmacy Practice + Business. While most of the mutated proteins were resistant to nirmatrelvir, they also showed drastically reduced enzymatic activity, suggesting they might impair viral replication and may not be as competitive as the wild-type virus. Read: Diabetes medications protect against blinding diseases “Significantly, several mutants showed signs they could mutate in a way that would make the virus become more drug resistant but at the same time maintaining the Mpro enzymatic activity at the similar level as the wild-type,” he said. This means a drug-resistant mutant virus could replicate. In a Rutger’s press release, Dr. Wang stated “doctors should reserve Paxlovid for the highest risk patients, the ones who need it most, because if Paxlovid is widely used, it will mostly destroy the variants it can treat, and the variants it cannot treat will become dominant.” He said the finding wasn’t a surprise because viruses commonly mutate quickly and evolve immunity to monotherapy treatments that bind to only one protein. Treatments with multiple drugs which bind to multiple target proteins on a virus, tend to maintain efficacy for longer because the virus must simultaneously mutate in several places to develop resistance. Read: Non-diabetics can have more complications from surgery than diabetics

Some SARS-CoV-2 variants showing signs of becoming resistant to Paxlovid

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