Specific inhibition of herpes simplex virus DNA polymerase by helical peptides corresponding to the subunit interface

Paul Digard, K. P. Williams, Preston Hensley, Ian S Brooks, Charles E Dahl, Donald M Coen

Research output: Contribution to journalArticlepeer-review

Abstract

The herpes simplex virus DNA polymerase consists of two subunits--a catalytic subunit and an accessory subunit, UL42, that increases processivity. Mutations affecting the extreme C terminus of the catalytic subunit specifically disrupt subunit interactions and ablate virus replication, suggesting that new antiviral drugs could be rationally designed to interfere with polymerase heterodimerization. To aid design, we performed circular dichroism (CD) spectroscopy and analytical ultracentrifugation studies, which revealed that a 36-residue peptide corresponding to the C terminus of the catalytic subunit folds into a monomeric structure with partial alpha-helical character. CD studies of shorter peptides were consistent with a model where two separate regions of alpha-helix interact to form a hairpin-like structure. The 36-residue peptide and a shorter peptide corresponding to the C-terminal 18 residues blocked UL42-dependent long-chain DNA synthesis at concentrations that had no effect on synthesis by the catalytic subunit alone or by calf thymus DNA polymerase delta and its processivity factor. These peptides, therefore, represent a class of specific inhibitors of herpes simplex virus DNA polymerase that act by blocking accessory-subunit-dependent synthesis. These peptides or their structures may form the basis for the synthesis of clinically effective drugs.
Original languageEnglish
Pages (from-to)1456-60
Number of pages5
JournalProceedings of the National Academy of Sciences
Volume92
Issue number5
Publication statusPublished - 28 Feb 1995

Keywords

  • Amino Acid Sequence
  • Binding Sites
  • Circular Dichroism
  • DNA, Viral/biosynthesis
  • DNA-Directed DNA Polymerase/antagonists & inhibitors
  • Exodeoxyribonucleases/antagonists & inhibitors
  • Macromolecular Substances
  • Molecular Sequence Data
  • Peptides/chemistry
  • Peptides/pharmacology
  • Protein Structure, Secondary
  • Simplexvirus/enzymology
  • Structure-Activity Relationship
  • Viral Proteins/chemistry
  • Viral Proteins/metabolism
  • Virus Replication

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