Pfizer’s New COVID-19 Antiviral Heads Into Clinical Trials

Pharmaceutical Pfizer has begun phase 1 clinical testing of PF-07304814, a small molecule that could be used to fight SARS-CoV-2, the virus that causes COVID-19. The compound targets 3CL protease, an enzyme that coronaviruses use to assemble and multiply. Cleaning up that bit of self-replicating machinery can turn off coronaviruses like SARS-CoV-2. If approved, PF-07304814 would be the first antiviral drug to target this protein.

“We believe that this potential first-of-its-kind protease inhibitor may provide us with the best opportunity to show significant antiviral activity to help treat COVID-19 patients,” said Mikael Dolsten, Chief Scientific Officer at Pfizer, during a video presentation to investors on September 19. fifteen.

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

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

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reported their results on the BioRxiv prepress server (2020, DOI: 10.1101 / 2020.09.12.293498), but the report has not yet been peer-reviewed.

The Pfizer team and their co-workers also tested PF-00835231’s ability to combat SARS-CoV-2 along with remdesivir, the Gilead Sciences antiviral that received the US Emergency Use Authorization in May. To treat COVID-19. Remdesivir targets a different protein, the SARS-CoV-2 RNA-dependent RNA polymerase. Because combination antiviral therapies may be more effective and more easily evade resistance, the researchers thought that additional therapy could potentiate the effects of remdesivir. So far, only remdesivir has been shown to shorten hospital stays.

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

Like remdesivir, PF-07304814 must be administered 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 antiviral for SARS-CoV-2 that Merck & Co. authorized. May. “The pressing need now continues to be the development of orally available agents, which can be widely used to treat people infected with COVID-19 and for prophylaxis of uninfected people 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 the broad antiviral activity of PF-00835231 looks promising, but notes that the projected effective dose (500 mg / day) is high.