New protease inhibitor outperforms Paxlovid in protecting lungs of mice with COVID

A new oral drug developed by researchers at Stanford University may be superior to Pfizer’s Paxlovid at reducing the severity of COVID-19, at least in mice. 

In a study published March 13 in Science Translational Medicine, Stanford scientists described how they developed a drug called ML2006a4, which they claimed in a press release was on par with Paxlovid at preventing mice from dying of COVID-19 and was better at protecting the animals’ lungs and lowering the overall viral load in their bodies. They’re now looking to expand the preclinical studies with the hope of eventually testing the drug in humans. 

“We’re very excited how far we’ve come and how successful our drug discovery has been on a shoestring budget,” senior author Michael Lin, M.D., Ph.D., said in the release. “We hope to see this promising compound developed further to stay ready for what SARS-CoV-2 throws at us next.” 

The new paper describes how the researchers built ML2006a4 from the template of an antiviral called boceprevir, which is used to treat hepatitis C. Like the drugs that make up Paxlovid—nirmatrelvir and ritonavir—boceprevir is a protease inhibitor, meaning that it works by targeting enzymes called proteases that viruses use to replicate.

In September 2020, the research team showed that the drug fit pretty well into the protease site of SARS-CoV-2. Those same findings also formed the basis of Paxlovid, according to the researchers. 

The researchers added carbon, nitrogen and oxygen atoms to several boceprevir-based compounds before testing the different iterations against SARS-CoV-2 particles, ultimately leading them to ML2006a4. They then gave mice infected with the virus twice-daily doses of the drug alongside ritonavir, which in Paxlovid is used to boost its efficacy of nirmatrelvir by blocking its metabolism in the liver. Another group of mice received the Paxlovid combination, while a third was treated only with ritonavir as a control. 

Mice in the ritonavir-only group all died within five days of infection, while those that received Paxlovid or ML2006a4 plus ritonavir completely recovered without weight loss or other complications from their illness. At six days post infection, the viral RNA load of the mice that received the combination with ML2006a4 was lower than in those that were treated with Paxlovid. Furthermore, the mice in the Paxlovid group had some degree of lung injury at two days post infection that hadn’t completely resolved by Day 6. In contrast, the ones that received the ML2006a4 combination had “minimal” injury on Day 2 and “rapid regeneration” by Day 6, the study said.

“In summary, ML2006a4 was as efficacious as [Paxlovid] in promoting survival of mice with SARS-CoV-2 and provided superior viral RNA suppression,” the researchers wrote in the paper. 

Assays run by the Stanford team helped explain why. ML2006a4 is a better fit than Paxlovid for its target: The drug has a 20-fold higher binding affinity for the coronavirus protease than nirmatrelvir, so it clings to the virus—and thus stops it from replicating—for much longer. 

Given that ML2006a4 may be more potent than Paxlovid, it could potentially be given in smaller, less frequent doses, the researchers noted in the release. That staying power might also eliminate the need to pair it with ritonavir—a significant benefit over Paxlovid for patients with comorbidities who are treated with other drugs. Ritonavir is the reason providers temporarily adjust the doses of some drugs or even remove them altogether for the treatment period, which comes with risks of its own. 

While the researchers will still need to test that hypothesis in future studies, they’re already working on ways to improve ML2006a4’s potency and duration, they said in the release. They’re also seeking additional investment outside of the small grants they’ve received for early-stage drug discovery.