Could This Molecule Be ‘Checkmate’ for Coronaviruses?

A team of scientists from Gladstone Institutes and UC San Francisco (UCSF) has developed new antiviral drug candidates that show great promise against SARS-CoV-2, the virus that causes COVID-19, and may also be effective against other less prevalent but much more deadly coronaviruses.

In preclinical testing, the compounds performed better than the antiviral drug Paxlovid against SARS-CoV-2 and Middle East Respiratory Syndrome (MERS), a virus that periodically causes deadly outbreaks around the world.

“These compounds could inhibit coronaviruses in general, giving us a head start against the next pandemic,” says Charles Craik, PhD, UCSF professor of pharmaceutical chemistry and co-corresponding author of the paper, which was published in Science Advances. “We need to get them across the finish line and into clinical trials.”

The discovery came out of UCSF’s Antiviral Drug Discovery (AViDD) Center for Pathogens of Pandemic Concern, which is led by Nevan Krogan, PhD, director of the UCSF Quantitative Biosciences Institute (QBI) and senior investigator at Gladstone.

From Virtual to Real-World Drug Candidates

Three years ago, the UCSF AViDD grant supercharged the efforts of the QBI Coronavirus Research Group (QCRG), which was founded in 2020 by Krogan. From this group, he assembled hundreds of scientists from 43 labs across UCSF, Gladstone, and a wide range of domestic and international institutions.

“COVID was our wake-up call to apply all our resources and know-how toward new therapies and future pandemic preparedness,” says Krogan, UCSF professor of cellular and molecular pharmacology, co-author of the paper, and a leading expert on the biology of infectious disease.

For the project that led to the new SARS-CoV-2 drug candidates, Krogan and Craik, who had experience designing drugs against HIV, partnered with Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology, as well as the UCSF labs of Adam Renslo, PhD, Brian Shoichet, PhD, and Kliment Verba, PhD.

The group focused on the major protease (MPro), a type of enzyme that breaks proteins into smaller pieces like a pair of molecular scissors. SARS-CoV-2 uses MPro to trim viral proteins into usable parts, which the virus then uses to replicate in human cells. Viral proteases have often been the target of attempts to make antiviral drugs, most notably for HIV.

The team first identified a few dozen molecular structures, out of millions, that mildly blocked MPro, providing a starting point for developing real-world drug candidates. They then synthesized hundreds of new molecules based on the virtual molecules, and tested them against MPro in the laboratory.

“We spent 18 months going back and forth with different molecules that fit reasonably well inside of MPro, but were still mediocre at blocking it,” Craik says. “Our progress stalled. Something had to give.”

After some time, the scientists found a way to make the molecules fit more snugly into the “active site” of MPro, blocking its ability to cut proteins, like jamming open a pair of scissors. Finally, the team found two molecules that weren’t just a perfect fit for MPro—they were glued within the jaws of the scissors.

“This was our lucky break and gave us some very special molecules,” says Craik. “They only react when they’re already inside this viral protease, but not to any of our own human proteases, giving us hope that they could have minimal side effects in people.”

A New Generation of Effective Antivirals

With rising confidence that the two new molecules effectively blocked MPro, Ott, a virologist, tested them against live SARS-CoV-2, first in petri dishes and then in mice.

Ott had tested hundreds of drug candidates against SARS-CoV-2 by this point.

“It’s very challenging to fight viruses in general, let alone SARS-CoV-2, but these new compounds were some of the best—if not the best—we had ever seen, in terms of eliminating infection,” says Ott, who is a co-corresponding author of the paper.

“These new compounds were some of the best—if not the best—we had ever seen, in terms of eliminating infection.”

Melanie Ott, MD, PhD

The two drug candidates looked promising as disease therapies. They potently blocked their target; they traveled efficiently through the body, ensuring they reached their target; and, at least in mice, they appeared safe.

In a follow-up experiment, a further-optimized version of the molecules effectively blocked variants of SARS-CoV-2 like Delta, as well as MERS, a less prevalent but much more deadly coronavirus.

The team believes its drug candidates, once shepherded through clinical trials to demonstrate safety in humans, could be kept “on the shelf” ready to fight the next pandemic caused by a coronavirus.

“These compounds are easy to modify and should be easy to manufacture,” says Renslo, who is also a co-corresponding author of the paper. “AViDD enabled us to discover important new counter measures for an important class of viral pathogens. It’s critical that we see this project through to clinical studies to ensure we’re better prepared for the next pandemic.”

Read the original news release by UC San Francisco.