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J Biol Chem, Vol. 275, Issue 1, 472-478, January 7, 2000

Secondary Structure and Structure-Activity Relationships of Peptides Corresponding to the Subunit Interface of Herpes Simplex Virus DNA Polymerase*

Kristie Grove BridgesDagger §, Qingxin HuaDagger , Michael R. Brigham-Burkepar , John D. Martin**, Preston Hensleypar Dagger Dagger , Charles E. Dahl§, Paul Digard§§§, Michael A. Weiss, and Donald M. Coen§¶¶

From the § Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, the  Departments of Biochemistry and Molecular Biology and Chemistry, Center for Molecular Oncology, University of Chicago, Chicago, Illinois 60639-5914, and the Departments of par  Structural Biology and ** Protein Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406

The interaction of the catalytic subunit of herpes simplex virus DNA polymerase with the processivity subunit, UL42, is essential for viral replication and is thus a potential target for antiviral drug discovery. We have previously reported that a peptide analogous to the C-terminal 36 residues of the catalytic subunit, which are necessary and sufficient for its interaction with UL42, forms a monomeric structure with partial alpha -helical character. This peptide and one analogous to the C-terminal 18 residues specifically inhibit UL42-dependent long chain DNA synthesis. Using multidimensional 1H nuclear magnetic resonance spectroscopy, we have found that the 36-residue peptide contains partially ordered N- and C-terminal alpha -helices separated 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 their ability to inhibit long-chain DNA synthesis and by circular dichroism for secondary structure. The results identify structural aspects and specific side chains that appear to be crucial for interacting with UL42. These findings may aid in the rational design of new drugs for the treatment of herpesvirus infections.

* This work was supported by National Institutes of Health Grants AI26077 and A119838 (to D. M. C.), AI10111 (to K. G. B.) and CA63485 (to M. A. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger The first two authors contributed equally to this work.

Dagger Dagger Present address: Protein Chemistry, Central Research Division, Pfizer, Inc., Eastern Point Rd., Groton, CT 06340.

§§ Present Address: Dept. of Pathology, Division of Virology, University of Cambridge, UK.

¶¶ To whom correspondence should be addressed.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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