SPECIFIC-INHIBITION OF HERPES-SIMPLEX VIRUS-DNA POLYMERASE BY HELICALPEPTIDES CORRESPONDING TO THE SUBUNIT INTERFACE

The herpes simplex virus DNA polymerase consists of two subunits - a c atalytic subunit and an accessory subunit, UL42, that increases proces sivity, Mutations affecting the extreme C terminus of the catalytic su bunit specifically disrupt subunit interactions and ablate virus repli cation, suggesting that new antiviral drugs could be rationally design ed to interfere with polymerase heterodimerization, To aid design, we performed circular dichroism (CD) spectroscopy and analytical ultracen trifugation studies, which revealed that a 36-residue peptide correspo nding to the C terminus of the catalytic subunit folds into a monomeri c structure with partial ar-helical character, Co studies of shorter p eptides were consistent with a model where two separate regions of alp ha-helix interact to form a hairpin-like structure, The 36-residue pep tide and a shorter peptide corresponding to the C-terminal 18 residues blocked UL42-dependent long-chain DNA synthesis at concentrations tha t had no effect on synthesis by the catalytic subunit alone or by calf thymus DNA polymerase delta and its processivity factor, These peptid es, therefore, represent a class of specific inhibitors of herpes simp lex virus DNA polymerase that act by blocking accessory-subunit-depend ent synthesis, These peptides or their structures may form the basis f or the synthesis of clinically effective drugs.