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Drug Discovery

Pfizer’s novel COVID-19 antiviral heads to clinical trials

The small molecule targets coronavirus 3CL protease and is active against multiple coronaviruses in cell studies

by Bethany Halford
September 17, 2020

Structures of PF-07304814 and PF-00835231

Drugmaker Pfizer has begun Phase 1 clinical tests of PF-07304814, a small molecule that could be used to fight SARS-CoV-2, the virus that causes COVID-19. The compound targets the 3CL protease, an enzyme that coronaviruses use to assemble themselves and multiply. Mucking up that bit of self-replication machinery can shut down coronaviruses like SARS-CoV-2. If approved, PF-07304814 would be the first antiviral drug to target this protein.

“We believe this potential first-in-class protease inhibitor may give us the best opportunity to show meaningful antiviral activity to help treat COVID-19 patients,” Mikael Dolsten, Pfizer’s Chief Scientific Officer, said during a video presentation to investors on Sept. 15.

PF-07304814 contains a phosphate group that makes the compound soluble and gets cleaved by alkaline phosphatase enzymes in tissue, releasing the active antiviral PF-00835231. Pfizer chemists first discovered that active compound, which was designed to target the 3CL protease of SARS-CoV, during the 2002–2003 outbreak of severe acute respiratory syndrome (SARS). But infections petered out and the compound, along with a collection of other potential coronavirus antivirals, was shelved.

The 3CL protease of SARS-CoV is very similar to that of SARS-CoV-2, and the two proteases’ active sites are identical, so Pfizer scientists and their collaborators decided to see how it fared in cellular tests against SARS-CoV-2.

Not only did PF-00835231 show activity against two strains of SARS-CoV-2, but it was also able to kill other coronaviruses in cells. “This suggests we have a pan-coronavirus protease inhibitor,” Dolsten said. The researchers reported their results on the preprint server BioRxiv (2020, DOI: 10.1101/2020.09.12.293498), but the report has not yet been peer-reviewed.

The Pfizer team and coworkers also tested PF-00835231’s ability to fight SARS-CoV-2 alongside remdesivir, Gilead Sciences’ antiviral that in May was granted Emergency Use Authorization in the US to treat COVID-19. Remdesivir targets a different protein, SARS-CoV-2’s RNA-dependent RNA polymerase. Because combination antiviral therapies can be more effective and more readily evade resistance, the researchers thought an additional therapy could boost remdesivir’s effects. So far, remdesivir has only been shown to shorten hospital stays.

The team found that in cells, remdesivir and PF-00835231 work synergistically. “These in vitro data suggest that you may be able to get the same control of the virus with lower concentration of each compound when used in combination,” Dolsten said.

Like remdesivir, PF-07304814 must be given intravenously. This will limit its use to hospital settings, says Dennis C. Liotta, an expert in antiviral therapies and executive director of the Emory Institute for Drug Development, which developed an orally-available SARS-CoV-2 antiviral that Merck & Co. licensed in May. “The pressing need now continues to be the development of orally-available agents, which can be used broadly to treat COVID-19 infected individuals and to prophylax uninfected individuals who are at risk of becoming infected,” he says.

Thanigaimalai Pillaiyar, a medicinal chemist at the University of Tübingen who develops coronavirus inhibitors, says that PF-00835231’s broad antiviral activity looks promising, but he notes that projected effective dose—500 mg/day—is high.


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