Vaccinia virus decapping enzyme D9 (D9)

Vaccinia virus decapping enzyme D9 is a viral Nudix hydrolase that catalyzes the hydrolysis of the 5′ cap structure (m⁷GpppN) from both host and viral mRNAs, thereby committing transcripts to degradation by cellular exonucleases such as Xrn1[1][3][5]. D9 is structurally distinct from host decapping enzymes, containing a conserved Nudix domain and a unique three-helix bundle domain inserted into the catalytic core, together forming a bipartite active site that recognizes the methylated guanosine cap via aromatic stacking interactions[1][3][5]. This activity enables poxviruses to shut off host protein synthesis, promote viral replication, and reduce accumulation of viral dsRNA, thereby dampening host innate immune responses[1][3]. D9 has broad substrate specificity, efficiently decapping both single- and double-stranded RNAs with little sequence preference at the first transcribed nucleotide position[1]. Recent studies indicate that D9, along with D10, is an essential virulence factor and represents a promising therapeutic target for antiviral drug development, with small-molecule and nucleotide analog inhibitors already showing specificity for D9 over related enzymes[7].

Other names

D9 decapping enzymeVaccinia D9VACV D9Poxvirus decapping enzyme D9

Competitive inhibition of decapping enzymatic activity, resulting in preservation of capped RNA and impairment of the virus’s ability to selectively degrade host and viral transcripts[7] Targeting the methylated guanosine cap-binding pocket or catalytic Nudix domain, disrupting the hydrolysis of the cap structure[1][5][7]