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UPenn researchers find drug that blocks multiple SARS-CoV-2 variants in mice

According to researchers at the University of Pennsylvania’s Perelman School of Medicine, the medication, diABZI, which promotes the body’s innate immune response, was extremely efficient in preventing severe COVID-19 in mice infected with SARS-CoV-2. The findings, which were published in Science Immunology this month, revealed that diABZI might be used to treat other respiratory coronaviruses as well.

“Few drugs have been identified as game-changers in blocking SARS-CoV-2 infection. This paper is the first to show that activating an early immune response therapeutically with a single dose is a promising strategy for controlling the virus, including the South African variant B.1.351, which has led to worldwide concern,” said senior author Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine and scientific director of the High-Throughput Screening (HTS) Core at Penn Medicine. “The development of effective antivirals is urgently needed for controlling SARS-CoV-2 infection and disease, especially as dangerous variants of the virus continue to emerge.”

The SARS-CoV-2 virus begins by attacking respiratory epithelial cells. The respiratory tract’s innate immune system identifies viral infections by recognizing their molecular patterns as the first line of defense against infection. Cherry and her colleagues began their research by looking at human lung cell lines that had been infected with HIV under a microscope. They discovered that the virus can hide, causing the immune system’s early identification and reaction to be delayed. The researchers hypothesized that they could be able to find medications that may trigger this immune response in respiratory cells sooner and prevent SARS-CoV-2 infection from becoming severe.

The researchers used high throughput screening to find antiviral agonists that would inhibit SARS-CoV-2 infection. They looked at 75 different medications that target sensing pathways in lung cells. They used microscopy to examine their impact on viral infection and found nine contenders, including two cyclic dinucleotides (CDNs), that greatly reduced infection by activating STING (the simulation of interferon genes).

Cherry and her colleagues opted to try a newly created small molecule STING agonist called diABZI, which is not licensed by the Food and Drug Administration but is now being evaluated in clinical trials to treat some tumors, because CDNs have low potency and make lousy medications, according to Cherry. The researchers discovered that diABZI effectively prevents SARS-CoV-2 infection in a variety of strains, including variant of concern B.1.351, via activating interferon signaling.

Finally, the researchers examined diABZI’s efficiency in transgenic mice infected with SARS-CoV-2.
DiABZI was delivered by nasal administration, as it needed to reach the lungs. DiABZI-treated animals lost much less weight than control mice, had considerably lower virus loads in their lungs and noses, and produced more cytokines —all supporting the finding that diABZI stimulates interferon for protective immunity.

The outcomes of the trial suggest that diABZI might be a successful therapy for SARS-CoV-2, preventing severe COVID-19 symptoms and the transmission of infection, according to Cherry. Furthermore, because diABZI has been found to limit the reproduction of human parainfluenza virus and rhinovirus in cultured cells, the STING agonist may be even more effective against other respiratory viruses.

“We are now testing this STING agonist against many other viruses,” Cherry said. “It’s really important to remember that SARS-CoV-2 is not going to be the last coronavirus that we will see and will need protection against.”

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