A unifying model for the broad-spectrum antiviral activity of a metalloenzyme of the inborn immune system named RSAD2 (viperin) is proposed based on the radical-SAM catalytic activity of the enzyme.

Viperin (RSAD2) is an antiviral radical S‐adenosylmethionine (SAM) enzyme highly expressed in different cell types upon viral infection. Recently, it has been reported that the radical‐SAM activity of viperin transforms cytidine triphosphate (CTP) to its analogue 3′‐deoxy‐3′,4′‐didehydro‐CTP (ddhCTP). Based on biochemical studies and cell biological experiments, it was concluded that ddhCTP and its nucleoside form ddhC do not affect the cellular concentration of nucleotide triphosphates and that ddhCTP acts as replication chain terminator. However, our re‐evaluation of the reported data and new results indicate that ddhCTP is not an effective viral chain terminator but depletes cellular nucleotide pools and interferes with mitochondrial activity to inhibit viral replication. Our analysis is consistent with a unifying view of the antiviral and radical‐SAM activities of viperin.