3-Deazaguanosine inhibits SARS-CoV-2 viral replication and reduces the risk of COVID-19 pneumonia in hamster

The COVID-19 pandemic highlighted the serious threat that coronaviruses have on public health. Because coronavirus continuously undergoes cross-species transmission, additional therapeutic agents and targets are urgently needed. Here, we show that a 3-deazapurine ribonucleoside, 3-Deazaguanosine (C³Guo, <b>2</b>), has potent antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unexpectedly, C³Guo (<b>2</b>) does not act as an inhibitor of RNA-dependent RNA polymerase (RdRp), which is the therapeutic target of two key nucleoside/nucleotide inhibitors approved for the treatment of COVID-19 (Remdesivir and Molnupiravir); instead, it seems to function by targeting the capping machinery of viral RNA. In hamsters infected with SARS-CoV-2, administration of <b>2</b> markedly reduced infectious viral titers, and prevented the development of COVID-19 pneumonia better than Molnupiravir. The potency of <b>2</b> against SARS-CoV-2 underscores its potential as an effective therapeutic agent for COVID-19 and future zoonotic coronavirus infections and raises the possibility of antiviral nucleoside analogs with alternative therapeutic targets to RdRp.