An early study in human cells found that an antiviral drug candidate, Pfizer Inc.'s PF-00835231, may be at least as potent as the drug remdesivir in blocking the reproduction of the virus that causes COVID-19.
PF-00835231 was shown in preliminary research conducted by NYU Grossman School of Medicine and Pfizer to block the action of the viral enzyme 3CLpro (Mpro). This protease cuts up precursors into working proteins necessary for the reproduction of pandemic virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Remdesivir works differently. As a nucleoside analog, it is woven into viral genetic material by the enzyme polymerase, which stops SARS-CoV-2 from copying itself inside human cells. Having been shown to reduce the length of hospital stays in patients with severe respiratory distress, Remdesivir is currently the only antiviral drug authorized for emergency use against COVID-19.
The new study found that, in one set of cell culture experiments, PF-00835231 was statistically more potent in blocking the replication of the pandemic virus (it took 3.3 times more remdesivir than PF-00835231 to fully suppress replication). In a second, arguably more relevant cell model (a 3D reconstruction of the human airway), the researchers found that both treatments were equally effective at blocking viral replication.
Posted online recently on the pre-print server bioRxiv, the study was done in cell culture (including the 3D airway model), cells grown for study in dishes of nutrients, researchers say. Such studies can reveal cellular mechanisms and provide a first look at drug potency, but whether PF-00835231 is effective as a treatment for SARS-CoV-2 infection would need to be confirmed ultimately in human clinical studies.
"Our study provides initial evidence that PF-00835231 is a potentially effective antiviral drug for COVID-19, and paves the way for further studies with this compound," says corresponding study author Meike Dittmann, PhD, assistant professor in the Department of Microbiology at NYU Langone Health. "As the two compounds, PF-00835231 and remdesivir, appear to work differently, the hope is that their effects may be additive, shutting down the viral life cycle at more than one step like the drug cocktails designed over decades to counter HIV and the hepatitis C virus."
The study results also demonstrated that PF-00835231 was effective at blocking SARS-CoV-2 replication in cell studies (in vitro) at 10 to 100 times lower concentrations than other drugs targeting 3CLpro that are currently in development, say the researchers. Still other experiments suggested that both PF-00835231 and remdesivir block viral replication of the two major viral lineages (clades) currently causing infections in the United States.
"While many studies are underway, the current arsenal of specific antiviral drugs against SARS-CoV-2 is extremely limited," says first author Maren de Vries, PhD, a postdoctoral scholar in Dittmann's lab. "The development of a diverse toolbox with different targets to combat SARS-CoV-2 will be important in controlling this disease."
The work is moving more quickly because of work done with 3CLpro inhibitors during the 2003 outbreak of SARS, a relative of the current pandemic virus, which infected 8,098 people globally and killed 774. At that time, the disease declined so quickly that clinical studies were not practical, and so PF-00835231 was never tested clinically. The main protease of the viruses from the 2003 outbreak and the current pandemic are 96 percent identical at the level of their amino acid molecular building blocks, say the authors.
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