Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into an unprecedented global pandemic. Nucleoside analogs, such as Remdesivir and Favipiravir, can serve the first-line broad-spectrum antiviral drugs by targeting viral polymerases. However, underlying mechanisms for efficacies these are far from well understood. Here, we reveal that a pyrazine derivative, could be incorporated RNA products mimicking both adenine guanine nucleotides. This drug thus inhibits replication mainly inducing mutations in progeny RNAs, different or other RNA-terminating nucleoside analogs impair elongation products. We further determined cryo-EM structure Favipiravir bound to replicating polymerase complex SARS-CoV-2 pre-catalytic state. provides missing snapshot visualizing catalysis dynamics polymerase, reveals unexpected base-pairing pattern between pyrimidine residues may explain its capacity These findings shed light on mechanism provide rational basis developing combat