Drugmaker Pfizer has initiated phase 1 clinical trials of PF-07304814, a small molecule that can be used to fight SARS-CoV-2, the virus that causes COVID-19. The compound targets 3CL protease, an enzyme that coronaviruses themselves use to assemble and multiply. That bitting of the self-replicating machinery can harbor coronaviruses such as SARS-CoV-2. If approved, PF-07304814 would be the first antiviral drug to target this protein.
Mikael Dolsten, Chief Scientific Officer at Pfizer said during a video presentation to investors on Sept, “We believe this potential first-in-class protease inhibitor is showing us meaningful antiviral activity to help treat COVID-19 patients.” The best chance you can. ” 15.
PF-07304814 contains a phosphate group that makes the compound soluble and is cleaved by the alkaline phosphate enzyme in the tissue, releasing the active antiviral PF-00835231. Pfizer chemists first discovered that the active compound, which was designed to target the 3CL protease of SARS-CoV during the 2002–05 outbreak of severe acute respiratory syndrome (SARS). But with the collection of other possible coronovirus antivirals, infections and petries were excluded.
The 3CL protection of SARS-CoV-3 is very similar to SARS-CoV-2, and the two proteases have similar active sites, so Pfizer scientists and their colleagues decided to see that this SARS-CoV-2 Was ahead in cellular tests? .
Not only did PF-00835231 show activity against two strains of SARS-CoV-2, but it was also capable of killing other coronaviruses in cells. “This suggests that we have a pan-coronavirus protease inhibitor,” Dolston said. The researchers reported their results on Preprint Server Biorexiv (2020, DOI: 10.1101 / 2020.09.12.293498), but the report has not yet been peer-reviewed.
The Pfizer team and colleagues also tested PFS-00835231 as an antiviral fighting ability of SARS-COV-2 as well as Remedisvir, Gilead Sciences, in May to treat COVID-19 in the US with Emergency Use Authorization was given. Remedisvir targets RNA-dependent RNA polymerase of a different protein, SARS-CoV-2. Because the combination of antiviral therapy may be more effective and more easily developed resistance, the researchers thought that an additional therapy might promote the effects of Remedisavir. Until now, RemedyShive has only been shown to be in hospital.
The team found that in cells, remedisvir and PF-00835231 work synergistically. “In vitro data suggest that you may be able to achieve equal control of the virus with lower concentrations of each compound when used in combination,” Dolston said.
Like Remedswear, PF-07304814 should be given intravenously. Dennis C., specialist in antiviral therapy and executive director of the Emory Institute for Drug Development. This would limit its use in a hospital setting, says Liotta, who licensed an orally available SARS-CoV-2 antiviral – Merck & Co. May. “Pressure is now needed in the development of orally available agents that can be used to treat broadly COVID-19 infected individuals and asymptomatic individuals who are at risk of infection,” he says. it is said.
Thanigimalai Pillaiyar, a medicinal chemist at the University of Tuniben, who develops coronovirus inhibitors, says the broad antiviral activity of PF-00835231 looks promising, but she notes that the effective dose — 500 mg / day — is high.
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