A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection

Coronaviruses are a family of RNA viruses that cause acute and chronic diseases of the upper and lower respiratory tract in humans and other animals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged coronavirus that has led to a global pandemic, causing a severe respiratory disease known as coronavirus disease 2019 (COVID-19) with substantial morbidity and mortality worldwide. The development of antiviral therapeutics is urgently needed while vaccine programs roll out worldwide. Here, we describe a diamidobenzimidazole compound, diABZI-4, that activates stimulator of interferon genes (STING) and is highly effective in limiting SARS-CoV-2 replication in cells and animals. diABZI-4 inhibited SARS-CoV-2 replication in lung epithelial cells. Administration of diABZI-4 intranasally before or even after virus infection conferred complete protection from severe respiratory disease in K18-ACE2 transgenic mice infected with SARS-CoV-2. Intranasal delivery of diABZI-4 induced a rapid short-lived activation of STING, leading to transient proinflammatory cytokine production and lymphocyte activation in the lung associated with inhibition of viral replication. Our study supports the use of diABZI-4 as a host-directed therapy that mobilizes antiviral defenses for the treatment and prevention of COVID-19.

Automated summary

This study describes a compound, diABZI-4, that activates stimulator of interferon genes (STING) and effectively limits SARS-CoV-2 replication in cells and animals. The administration of diABZI-4 intranasally in mice provided complete protection from severe respiratory disease caused by SARS-CoV-2. It induces a rapid, short-lived activation of STING, leading to transient proinflammatory cytokine production and lymphocyte activation in the lung, ultimately inhibiting viral replication. The study supports the use of diABZI-4 as a host-directed therapy for the treatment and prevention of COVID-19.