Researchers at Penn Medicine have identified a drug that is effective at blocking multiple SARS-CoV-2 variants in mice. The drug, named diABZI, activates the innate immune response and has been shown to be highly effective at preventing severe COVID-19 symptoms in studies on mice.
SARS-CoV-2 targets epithelial cells in the upper respiratory tract, gains entry to the cells, and hijacks the cellular machinery to reproduce. The innate immune system acts as a first line of defense and can recognize the viral pathogens from their molecular patterns, but with SARS-CoV-2 the innate immune system is hampered.
Sara Cherry PhD, a professor of Pathology and Laboratory Medicine and scientific director of the High-Throughput Screening (HTS) Core at Penn Medicine, and her team studied human lung cell lines that had been infected with SARS-CoV-2 and found that the virus is capable of delaying the early recognition and response of the innate immune system. They hypothesized that small molecules with drug-like properties could potentially be administered in the early stages of infection to activate the innate immune system and stop the SARS-CoV-2 virus from hiding, and by so doing, prevent severe COVID-19 symptoms.
“SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection,” explained the researchers.
The researchers performed high throughput screening of 75 drug-like small molecules known to target sensing pathways in lung cells and investigated the effects of those molecules on infected cells under the microscope. They identified nine potential molecules, including two cyclic dinucleotides (CDNs), that suppressed infection by activating the stimulation of interferon genes (STING).
CDNs to not make effective drugs as they have low potency, so the researchers also tested a recently developed small molecule STING agonist – diABZI. While diABZI has yet to be approved for use by the FDA, it is currently being used in clinical trials as a potential cancer treatment. The researchers found that diABZI was effective at inhibiting several strains of SARS-CoV-2 in vitro by stimulating interferon signaling.
The researchers then tested the effectiveness of diABZI in transgenic mice infected with SARS-CoV-2 and found the symptoms of COVID-19 were less severe after a single treatment. Treated mice suffered lower weight loss than control mice, the viral load in the lungs of the treated mice was significantly lower, and they had increased cytokine production, suggesting diABZI was stimulating interferon.
Potentially, individuals infected with SARS-CoV-2 could be provided with a single dose of diABZI to prevent serious COVID-19 symptoms from developing. Cherry also pointed out that diABZI was effective at inhibiting human parainfluenza virus and rhinovirus replication in cultured cells, so could prove to be an effective treatment for other human respiratory viruses.
The researchers are now investigating the effectiveness of the STING agonist against other respiratory viruses.
You can read more about the study in the paper – Pharmacological activation of STING blocks SARS-CoV-2 infection – which was recently published in Science Immunology. DOI: 10.1126/sciimmunol.abi9007