Secondary structure and structure-activity relationships of peptides corresponding to the subunit interface of herpes simplex virus DNA polymerase

The interaction of the catalytic subunit of herpes simplex virus DNA polyme rase with the processivity subunit, UL42, is essential for viral replicatio n and is thus a potential target for antiviral drug discovery. We have prev iously reported that a peptide analogous to the C-terminal 36 residues of t he catalytic subunit, which are necessary and sufficient for its interactio n with UL42, forms a monomeric structure with partial alpha-helical charact er. This peptide and one analogous to the C-terminal 18 residues specifical ly inhibit UL42-dependent long chain DNA synthesis. Using multidimensional H-1 nuclear magnetic resonance spectroscopy, we have found that the 36-resi due peptide contains partially ordered N- and C-terminal alpha-helices sepa rated by a less ordered region. A series of "alanine scan" peptides derived from the C-terminal 18 residues of the catalytic subunit were tested for t heir ability to inhibit long-chain DNA synthesis and by circular dichroism for secondary structure. The results identify structural aspects and specif ic side chains that appear to be crucial for interacting with UL42. These f indings may aid in the rational design of new drugs for the treatment of he rpesvirus infections.