The drug diABZI – which activates the body’s innate immune response – was highly effective in preventing severe COVID-19 in mice that were infected with SARS-CoV-2, according to scientists in the Perelman School of Medicine at the University of Pennsylvania.
The findings, published this month in Science Immunology, suggest that diABZI could also treat other respiratory coronaviruses.
“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, Ph.D., 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 initially targets epithelial cells in the respiratory tract. As the first line of defense against infection, the respiratory tract’s innate immune system recognizes viral pathogens by detecting their molecular patterns. Cherry and her research team first sought to better understand this effect by observing human lung cell lines under the microscope that had been infected with SARS-CoV-2.
They found that the virus is able to hide, delaying the immune system’s early recognition and response. The researchers predicted that they may be able to identify drugs – or small molecules with drug-like properties – that could set off this immune response in the respiratory cells earlier and prevent severe SARS-CoV-2 infection.
To identify antiviral agonists that would block SARS-CoV-2 infection, the researchers performed high throughput screening of 75 drugs that target sensing pathways in lung cells.
They examined their effects on viral infection under microscopy and identified nine candidates – including two cyclic dinucleotides (CDNs) – that significantly suppressed infection by activating STING (the simulation of interferon genes).
Since CDNs have low potency and make poor drugs, according to Cherry, she and her team decided to also test a newly-developed small molecule STING agonist called diABZI, which is not approved by the Food and Drug Administration but is currently being tested in clinical trials to treat some cancer.
The researchers found that diABZI potently inhibits SARS-CoV-2 infection of diverse strains, including variant of concern B.1.351, by stimulating interferon signaling.
Finally, the researchers tested the effectiveness of diABZI in transgenic mice that had been infected with SARS-CoV-2. Because the drug needed to reach the lungs, diABZI was administered through a nasal delivery.
diABZI-treated mice showed much less weight loss than the control mice, had significantly-reduced viral loads in their lungs and nostrils, and increased cytokine production – all supporting the finding that diABZI stimulates interferon for protective immunity.
Cherry said that the study’s findings offer promise that diABZI could be an effective treatment for SARS-CoV-2 that could prevent severe COVID-19 symptoms and the spread of infection. Additionally, since diABZI has been shown to inhibit human parainfluenza virus and rhinovirus replication in cultured cells, the STING agonist may be more broadly 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.”
As of January 2021, the recently emerged severe-acute respiratory syndrome coronavirus 2 has led to over 2 million deaths and over 100 million infections globally (1). SARS-CoV-2 is a member of the Coronaviridae family of viruses. Respiratory infections with SARS-CoV-2 can result in asymptomatic, mild or severe forms of a disease known as COVID-19.
More severe cases of COVID-19 result in death due to acute respiratory distress syndrome and damage to the alveolar lumen (2). Currently, there are few treatment options for COVID-19 patients. The antiviral RNA-dependent polymerase inhibitor remdesivir reduces length of hospitalization and deaths from COVID-19 (3).
In addition, the steroid dexamethasone has also been approved for use in severe COVID-19 (4). To date numerous efficacious vaccines have been developed and rolled out (5, 6). Despite these advances additional antiviral therapeutics will be required for the treatment of future endemic infections.
An ongoing global effort is now underway to identify and develop new antiviral and anti-inflammatory therapeutics to reduce COVID-19 related hospitalizations and deaths.
The ER-resident adaptor protein Stimulator of Interferon Genes is a key signaling molecule that is activated following cytosolic DNA detection. Cyclic GMP-AMP synthase is an innate immune sensor of cytosolic DNA. Upon DNA binding cGAS converts ATP and GTP into the cyclic dinucleotide cGAMP, which in turn binds and activates STING (7).
Conformational changes in STING lead to C-terminal phosphorylation of STING, dimerization, oligomerization and subsequent activation of autophagy, NF-κB, IRF3 and transcription of proinflammatory cytokines and type I IFNs (8–10). Activation of STING can elicit a potent anti-tumor response and the use of STING agonists in oncology alone or in combination with checkpoint blockade is an emerging therapeutic area (11–13).
A recent study has identified a new class of STING agonists with systemic in vivo activity. Diamidobenzimidazole based compounds are potent, specific activators of STING and possess superior stability, tissue penetrance and potency over traditional cyclic dinucleotide STING agonists (14).
While the therapeutic applications of STING agonists have been reported for use in oncology, the antiviral potential of STING agonists remains underexplored. Given the potent type I IFN response induced by diABZI compounds, we hypothesized that pharmacological activation of STING may elicit protection from SARS-CoV-2 infection.
We have identified a host-directed therapy that is efficacious for the treatment of SARS-CoV-2 infection. Pharmacological activation of STING in the lung during SARS-CoV-2 infection elicits a rapid short-lived antiviral response via type I IFNs, NF-κB driven cytokine production and lymphocyte activation resulting in inhibition of viral replication and prevention of severe respiratory disease. Use of diABZI-4 over other immunotherapies such as recombinant IFN offers several significant advantages including cost, enhanced stability, room temperature storage and potential for efficacy at low dose treatments.
SARS-CoV-2 is a respiratory pathogen which can infect ACE2 positive cells in the upper and lower respiratory tract. Type II alveolar cells are readily infected by SARS-CoV-2 and represent approximately 15% of alveolar cells. Type II alveolar cells are essential to produce surfactant proteins and support epithelial barrier integrity, innate immune responses and airway regeneration following lung insult (26). iAT2-ALI 3D cultures mimic the human airway and mirror host transcriptional responses to SARS-CoV-2 (27). diABZI-4 showed strong inhibition of SARS-CoV-2 replication in iAT2 cells and inhibited SARS-CoV-2-induced cell death of SP2 positive alveolar cells. Thus, the use of diABZI-4 in the human lung is predicted to be effective against SARS-CoV-2.
In vivo, diABZI-4 was efficacious against SARS-CoV-2 prior to and after infection. diABZI-4 administered 12 hours after SARS-CoV-2 infection provided comparable protection to diABZI-4 given as a pre-treatment. The infection of hACE2-transgenic mice with SARS-CoV-2 results in rapid weight loss and morbidity over a period of 6-8 days.
Thus, the relative time between infection and peak viral load is extremely short which provides limitations for the use of diABZI-4 to be administered therapeutically. Indeed, the use of other immunotherapies such as intranasal IFN or poly(I:C) are also limited by the rapid kinetics of SARS-CoV-2 infection.
Therapeutic utility of multiple doses of universal IFN or poly(I:C) in a hamster model of SARS-CoV-2 was also limited to 24 hours after infection (28). While type I IFNs play an essential role in initiating the adaptive immune response to SARS-CoV-2, they alone are not sufficient to control SARS-CoV-2 infection (29, 30). However, other reports in human studies have demonstrated an essential role for type I IFNs in preventing severe COVID-19 (31).
In support of this some clinical trials have reported positive results for use of IFN in the early stages of COVID-19 (32). STING activation triggers type I IFN production which mediates activation of CD8+ T-cell responses. However, in addition to type I IFN responses NF-κB and non-canonical autophagy are also induced downstream of STING (10). Indeed, recent studies have identified IFN-independent roles for STING in the control of DNA virus infection and anti-tumor immunity (33–35). In addition to SARS-CoV-2, diABZI-4 also conferred protection from IAV infection.
Thus, the host-directed immune response activated by diAZBI-4 may have broad treatment applications to other respiratory pathogens. Like other immunotherapies, future work will be required to determine the appropriate dose and means of delivery for the use of diABZI-4 in humans. Our study provides molecular and cellular characterization of diABZI-4 in the prevention of SARS-CoV-2 replication, treatment of COVID-19 and highlights its potential use as a treatment for COVID-19 and its potential for the treatment of future pandemics caused by respiratory pathogens in humans.
reference link : https://immunology.sciencemag.org/content/6/59/eabi9002
More information: Minghua Li et al, Pharmacological activation of STING blocks SARS-CoV-2 infection, Science Immunology (2021). DOI: 10.1126/sciimmunol.abi9007