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

  • Sci Immunol. 2021 May 18;6(59):eabi9002. doi: 10.1126/sciimmunol.abi9002.
Fiachra Humphries  1 ,  Liraz Shmuel-Galia  1 ,  Zhaozhao Jiang  1 ,  Ruth Wilson  1 ,  Philip Landis  2 ,  Sze-Ling Ng  2 ,  Krishna-Mohan Parsi  3 ,  Rene Maehr  3 ,  John Cruz  4 ,  Angel Morales-Ramos  2 ,  Joshi M. Ramanjulu  2 ,  John Bertin  2 ,  G. Scott Pesiridis  2 ,  Katherine A. Fitzgerald  1
Affiliations
  • 1. Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 2. Innate Immunity Research Unit. GlaxoSmithKline, Collegeville, PA, USA.
  • 3. Program in molecular medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 4. Department of pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
PMID: 34010139 DOI: 10.1126/sciimmunol.abi9002
Abstract

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. SARS-CoV-2 is a recently emerged coronavirus that has led to a global pandemic causing a severe respiratory disease known as COVID-19 with significant morbidity and mortality worldwide. The development of Antiviral therapeutics are urgently needed while vaccine programs roll out worldwide. Here we describe a diamidobenzimidazole compound, diABZI-4, that activates 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 which mobilizes Antiviral defenses for the treatment and prevention of COVID-19.

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