The Achilles’ heel of coronaviruses: targeting the 5’ Polyuridines tract of the antigenome to inhibit Mouse coronavirus-induced cell death

The current coronavirus pandemic situation is worsened by the rapidly-spreading SARS-CoV-2 virus variants. Identification of viral targets that are indispensable for the virus can be targeted to inhibit mutation-based new escape variant development. The 5’-polyU tract of the antigenome offers such a target. Host cells do not harbor 5’-polyU tracts on any of their transcripts, making the tract an attractive, virus-specific target. Inhibiting the 5’-polyU can limit the use of the tract as template to generate 3’ polyA tails of +RNAs of coronaviruses. Here, a modified DNA oligo with 3’ polyAs is used to target the 5-polyU tract in mouse coronavirus (MHV-A59). The oligo treatment in mouse 17CL-1 cells infected with MHV-A59 significantly prevented virus-induced cell deaths. This proof-of-concept result shows a unique mode of action against mouse coronavirus without affecting host cells, and can be used for the development of novel classes of drugs that inhibit coronavirus infection in host cells, specifically by the COVID-19-causing virus SARS-CoV-2. In addition, as the 5’-polyU tract is immediately generated upon infection, the tag can also be targeted for reliable early detection of viral infection.