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J. Biol. Chem., Vol. 281, Issue 26, 18193-18200, June 30, 2006

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Crystal Structure of the Herpes Simplex Virus 1 DNA Polymerase^*

From the Pfizer Inc., Groton, Connecticut 06340

Herpesviruses are the second leading cause of human viral diseases. Herpes Simplex Virus types 1 and 2 and Varicella-zoster virus produce neurotropic infections such as cutaneous and genital herpes, chickenpox, and shingles. Infections of a lymphotropic nature are caused by cytomegalovirus, HSV-6, HSV-7, and Epstein-Barr virus producing lymphoma, carcinoma, and congenital abnormalities. Yet another series of serious health problems are posed by infections in immunocompromised individuals. Common therapies for herpes viral infections employ nucleoside analogs, such as Acyclovir, and target the viral DNA polymerase, essential for viral DNA replication. Although clinically useful, this class of drugs exhibits a narrow antiviral spectrum, and resistance to these agents is an emerging problem for disease management. A better understanding of herpes virus replication will help the development of new safe and effective broad spectrum anti-herpetic drugs that fill an unmet need. Here, we present the first crystal structure of a herpesvirus polymerase, the Herpes Simplex Virus type 1 DNA polymerase, at 2.7 Å resolution. The structural similarity of this polymerase to other polymerases has allowed us to construct high confidence models of a replication complex of the polymerase and of Acyclovir as a DNA chain terminator. We propose a novel inhibition mechanism in which a representative of a series of non-nucleosidic viral polymerase inhibitors, the 4-oxo-dihydroquinolines, binds at the polymerase active site interacting non-covalently with both the polymerase and the DNA duplex.

Received for publication, March 15, 2006 , and in revised form, April 24, 2006.

The atomic coordinates and structure factors (code 2GV9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Pharmaceutical Research Inst., Bristol-Myers Squibb Co., Rte. 206 and Provinceline Rd., Princeton, NJ 08540.

³ Present address: Proteos, 4717 Campus Dr., Kalamazoo, MI 49008.

⁴ Present Address: 6916 Willson Dr., Kalamazoo, MI 49009.

⁵ Present address: University of Pittsburgh, Dept. of Molecular Genetics and Biochemistry, School of Medicine, 200 Lothrop St., BSTWR W1256, Pittsburgh, PA 15261.

⁶ Present address: PharmOptima LLC, 4717 Campus Dr., Kalamazoo, MI 49008.

¹ To whom correspondence should be addressed: Pfizer Inc., Exploratory Medicinal Sciences, Eastern Point Rd., Groton, CT 06340. Tel.: 860-686-6959; Fax: 860-686-2095; E-mail: shenping.liu{at}pfizer.com.

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