Specific inhibition of the interaction between pseudorabies virus DNA polymerase subunits UL30 and UL42 by a synthetic peptide

Abstract

Pseudorabies virus (PRV) is a ubiquitous and economically important swine alphaherpesvirus that causes devastating swine diseases worldwide. PRV-encoded DNA-dependent DNA polymerase, comprised of the catalytic subunit UL30 and the accessory subunit UL42, is essential for viral replication. PRV UL30 and UL42 act as a heterodimer with UL30 harboring inherent DNA polymerase activity and UL42 conferring processivity on the DNA polymerase holoenzyme. The formation of PRV UL30/UL42 heterodimer holoenzyme through protein-protein interactions is indispensable for viral replication. In work described here, we defined the key domains that mediate PRV UL30/UL42 interaction, and found that the 41 carboxy-terminal amino acids region of PRV UL30 is critical for its interaction with UL42. Intriguingly, a synthetic peptide corresponding to these 41 carboxy-terminal amino acid residues efficiently disrupted PRV UL30/UL42 interaction through competitively binding to UL42. These findings suggest that the peptides from the PRV DNA polymerase UL30/UL42 subunit interface may represent potential targets for designing a novel intervention strategy against PRV infection. This work further strengthens the concept that the herpesvirus DNA polymerase catalytic subunits utilize their extreme carboxy-terminal domains as a conserved mechanism to associate with their cognate accessory subunits, providing us the opportunity of designing novel antiviral agents against herpesvirus infection through disruption of the herpesvirus DNA polymerase subunit interactions.