USF Health researchers publish on naturally occurring mutations of SARS-CoV-2 main protease gaining resistance to nirmatrelvir

In the war against deadly viruses, the enemy often wears camouflage. The challenge is how to spot an elusive foe and declare victory before more lives are lost.

One promising weapon has been the COVID-19 medication Paxlovid, which was introduced for emergency use late last year with much promise as an effective drug in keeping infected people out of the hospital.

However, researchers from USF Health, Rutgers University, and Catholic University of America are investigating how mutations of SARS-CoV-2 develop resistance to nirmatrelvir – the main component of Paxlovid. Their research has been published on the on-line preprint server bioRxiv and is currently undergoing peer-review.

The emergence of SARS-CoV-2 variants with mutations in the main protease – or M^pro – have raised the alarm for the possibility of natural M^pro mutations, which make “nirmatrelvir less effective in treating COVID-19,’’ said Dr. Yu Chen, PhD, associate professor in the Department of Molecular Medicine in the Morsani College of Medicine at USF.

From left, Dr. Yu Chen and Dr. Eric Lewandowski.

Created by Pfizer, Paxlovid is taken orally and has proven to treat severe disease from SARS-CoV-2 infections, which often require hospitalization. Nearly 90 million people in the U.S. have been infected with COVID-19, and more than 1 million have died.

If the virus can bypass Paxlovid, experts say, they could lose a major therapy in battling the pandemic.

“While vaccines have been quite effective in preventing serious symptoms of COVID-19, the therapeutic options to treat it are very limited and only two oral drugs have been approved in the U.S. so far,’’ Dr. Chen added. “Resistance makes nirmatrelvir less effective in treating COVID-19.’’

Led by USF’s Dr. Chen and Dr. Jun Wang of the Department of Medicinal Chemistry at Rutgers, the team cloned and purified many M^pro mutant proteins that occurred in nature, and analyzed their biological activity, including how they interacted with nirmatrelvir.

“We found many of them retained significant activity of the original protein, while showing resistance to nirmatrelvir,’’ Dr. Chen said, adding that their activity was less affected by the drug. “We are currently combining some of these mutations to study whether several mutations together can allow the protein to be even more resistant to the drug.’’

Viruses tend to mutate quickly enough to evolve immunity to monotherapy treatments that bind to only one protein, said members of the Rutgers team. Combination treatments, with multiple drugs that bind to multiple target proteins on the virus, tend to maintain efficacy for much longer because the virus must simultaneously mutate in several places to develop resistance, the researchers said.

The jury is still out on how effective Paxlovid will be as the virus continues to mutate and begins to disarm the drug’s weaponry. Further research could change how these battles are fought, Dr. Chen said.

“By understanding how the protein can become resistant to the drug,’’ he added, “we can better design the next generation of drugs to make them more effective and less prone to resistance development.’’

Story by Kurt Loft