UCSF and Gladstone Institutes develop compounds with a 1,000,000-fold reduction in viral titers and 1,000 times effective concentration in the brain.
Investigator
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Two experimental antiviral compounds developed by researchers at the University of California, San Francisco, and Gladstone Institutes have shown superior performance to Paxlovid in preclinical testing against both SARS-CoV-2 and MERS. The findings, published in Science Advances, suggest the new compounds may offer broad protection against current and future coronaviruses.1
The compounds, AVI4516 and AVI4773, target the main protease of the virus, a key enzyme that enables viral replication. In mice, AVI4773 led to a more than one million-fold reduction in viral titers after just three doses and achieved drug concentrations in brain tissue more than one thousand times the effective dose within eight hours of oral administration. Both drugs were well distributed across tissues and appeared safe in animal models.1
The molecules showed strong pan-coronavirus activity and minimal off-target effects. AVI4516 did not significantly inhibit human proteases or major cytochrome P450 enzymes. It also worked synergistically with molnupiravir, an existing antiviral that targets RNA polymerase. Related analogs were effective against virus strains resistant to nirmatrelvir, the main component of Paxlovid.1
In the EurekAlert press release, Charles Craik, PhD, UCSF professor of pharmaceutical chemistry and co-corresponding author of the paper, said, “In three years, we’ve moved as fast as a pharmaceutical company would have, from start to finish, developing drug candidates against a totally new pathogen. These compounds could inhibit coronaviruses in general, giving us a head start against the next pandemic. We need to get them across the finish line and into clinical trials.”2
Researchers emphasized the urgency of advancing these compounds to clinical trials, especially given the termination of a key federal grant that supported their development. The team believes these candidates could serve as shelf-stable countermeasures for future coronavirus outbreaks and offer a much-needed backup as new variants emerge.1
Two new compounds, AVI4516 and AVI4773, showed stronger antiviral activity than Paxlovid against SARS-CoV-2 and MERS in animal models.
The drugs demonstrated broad pan-coronavirus protection, strong brain penetration, and synergy with molnupiravir, while avoiding off target effects.
Researchers are urgently pushing the compounds into clinical trials amid concerns over terminated federal funding that supported their rapid development.
Researchers emphasized the urgency of advancing these compounds to clinical trials, especially given the termination of a key federal grant that supported their development. The team believes these candidates could serve as shelf-stable countermeasures for future coronavirus outbreaks and offer a much-needed backup as new variants emerge.1
“COVID was our wake-up call to apply all our resources and know-how toward new therapies and future pandemic preparedness,” said Nevan Krogan, UCSF professor of cellular and molecular pharmacology, co-author of the paper, and a leading expert on the biology of infectious disease. “The AViDD funding, which is now in peril, was poised to help us produce potent and necessary antivirals in record time.”2
In other recent news, a phase 2 trial published in The Lancet found that nirmatrelvir ritonavir (Paxlovid) showed no statistically significant improvement in physical health outcomes for patients with Long COVID. Although it remains effective in reducing mortality among immunocompromised patients, its limited utility in addressing persistent symptoms and its frequent adverse effects underscore the need for more potent and targeted antiviral options.3
In contrast, AVI4516 and AVI4773 are novel main protease inhibitors that show enhanced potency, pan-coronavirus activity, and strong pharmacokinetics, including distribution to critical tissues like the brain. These compounds also remain effective against nirmatrelvir-resistant viral strains and exhibit synergy with molnupiravir, suggesting a next-generation therapeutic approach that could address some of the limitations seen with Paxlovid.
