A multidisciplinary team of researchers at the University of California, San Francisco (UCSF) and Gladstone Institutes has announced the development of new antiviral drug candidates showing exceptional promise against the virus that causes COVID-19, as well as other coronaviruses that pose future pandemic threats.
Advancing Beyond Existing Treatments
In rigorous preclinical testing, the newly developed compounds outperformed Paxlovid, the current frontline antiviral, against SARS-CoV-2 and the Middle East Respiratory Syndrome (MERS) virus. MERS, although less widespread, is known for causing periodic deadly outbreaks globally, making the discovery significant in broad coronavirus preparedness.
“In just three years, we moved as fast as a pharmaceutical company would have, from start to finish, developing drug candidates against a completely new pathogen,” said Charles Craik, PhD, UCSF professor of pharmaceutical chemistry and co-corresponding author of the study published April 23 in Science Advances. “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.”
Filling a Critical Gap in Pandemic Preparedness
This breakthrough was funded by the National Institute of Allergy and Infectious Diseases (NIAID) under a grant aimed at preparing for future coronavirus epidemics — a field where many pharmaceutical companies have since reduced investment. Despite the promising results, funding for the UCSF team’s antiviral drug candidates has recently been cut, putting the future of the project in jeopardy.
The research emerged from UCSF’s Antiviral Drug Discovery (AViDD) Center for Pathogens of Pandemic Concern, one of nine national centers created by NIAID in 2022 to bolster readiness for emerging infectious diseases. AViDD brought together hundreds of scientists globally, united in their mission to develop new therapies.
From Virtual Screening to Potent Drug Candidates
The drug discovery process began with the UCSF Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), founded in 2020 and comprising over 800 scientists from 43 institutions worldwide.
Leveraging expertise across UCSF and partner institutes, including Gladstone, Mount Sinai, Northwestern, MIT, and international collaborators, the team used Shoichet’s molecular docking software to virtually screen millions of molecules for interaction with the virus’s main protease (MPro). MPro is a viral enzyme that SARS-CoV-2 uses like molecular scissors to cleave viral proteins into functional pieces necessary for replication.
From this virtual screen, a shortlist of promising molecules was synthesized and tested in the lab. After 18 months of iterative testing and optimization, the researchers refined the compounds to improve their fit inside MPro’s active site — effectively jamming the molecular scissors.
Innovative Chemistry Drives Success
Postdoctoral researchers Gilles DeGotte, PhD, and Luca Lizzadro, PhD, led the molecular design and synthesis efforts, employing “click chemistry” to introduce molecular adapters that allowed rapid modification of the drug candidates for optimal enzyme binding.
Two standout molecules, AVI-4516 and AVI-4773, demonstrated a unique ability to irreversibly bind inside the viral protease without affecting human proteases, which minimizes potential side effects.
“This was our lucky break,” said Craik. “These molecules only react inside the viral enzyme, giving us hope for high specificity and safety in human treatments.”
Preclinical Success in Lab and Animal Models
Virologist Melanie Ott, PhD, tested the drug candidates against live SARS-CoV-2 in cell cultures and mouse models. The compounds showed exceptional efficacy in eliminating infection and good pharmacokinetics, ensuring they reach the target enzyme in the body.
Further optimization led to versions effective against multiple SARS-CoV-2 variants, including Delta, and the more lethal MERS coronavirus, highlighting their potential as broad-spectrum antivirals.
Preparing for Future Pandemics
The research team envisions these antiviral candidates as stockpiled therapies ready to be deployed quickly at the onset of future coronavirus outbreaks.
“These compounds are easy to modify and manufacture,” said Adam Renslo, PhD, co-corresponding author. “AViDD enabled us to develop vital new countermeasures for a critical class of viral pathogens. It’s crucial we advance these candidates to clinical trials to be better prepared for the next pandemic.”
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