Diaminobenzimidazoles Give SARS-CoV-2 a STING

Two research teams published back-to-back papers in Science Immunology indicating that diaminobenzimidazoles (diABZIs), a class of chemical compounds, treated SARS-CoV-2 infection and prevented serious disease in mice and human cells in vitro. Both studies point to diABZIs as a successful COVID-19 therapy for mobilizing protection and stopping viral replication after it has entered the body. DiABZIs, according to the writers, this have many advantages over comparable drugs, including lower cost, improved safety, room temperature storage, and the potential for efficacy even at low doses.

Minghua Li, PhD, a postdoc in Sara Cherry's lab at the University of Pennsylvania's Department of Pathology and Laboratory Medicine, and his colleagues demonstrated in human respiratory cell culture experiments that SARS-CoV-2 "cover" it self from the immune system. Interferons (IFNs), which are inflammatory proteins that prevent viral replication, are activated by the virus. The results are recorded in a report. “Pharmacological activation of STING blocks SARS-CoV-2 infection.”

SARS-CoV-2 delayed the response of bystander immune cells by avoiding IFN activation, leading the authors to believe that blocking immune pathways involved in IFN activation could help regulate SARS-CoV-2 infection. They screened a panel of 75 microbial ligands for antiviral innate immune players and discovered that molecules that activate STING—a main stimulator of IFN genes—were potent antiviral players.

In vitro human cell experiments and two separate mouse models of SARS-CoV-2 infection, they studied one kind of diABZI, a potent STING activator. By transiently inducing IFN signaling, the molecule effectively inhibited SARS-CoV-2 infection through models and experiments, including infections triggered by a variety of strains and variants. After a single intranasal administration of diABZI, RNA sequencing of immune cells in mouse lungs showed rapid activation of IFN signaling pathways. The researchers also discovered a significant overlap between orthologs of diABZI-induced genes in human respiratory epithelial cells and mouse lungs, indicating that the drug's clinical translation from mouse to human could be effective.

In the second paper, Fiachra Humphries, PhD, a postdoc in Kate Fitzgerald's lab at the University of Massachusetts Medical School's department of medicine's program in innate immunity, in collaboration with GlaxoSmithKline, studied a diABZI-4 variant of the same compound in a transgenic mouse model of SARS-CoV-2 infection. The molecule was extremely successful at inhibiting viral replication in lung epithelial cells, which are the virus's primary targets.

This work is published in the paper, “A novel diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection.”

STING activation was brief but effective in inhibiting viral replication by inducing transient inflammatory molecule development and lung immune cell activation. Mice were shielded from serious respiratory disease by administering diABZI-4 intranasally before and after virus infection.

Both groups are working on determining the best dosage and delivery mechanism for diABZIs in humans, as well as whether the lung-targeted therapy may be used to treat other respiratory pathogens including influenza.