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Journal of Virology, February 2003, p. 2349-2358, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2349-2358.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of Small Molecule Compounds That Selectively Inhibit Varicella-Zoster Virus Replication

Robert J. Visalli,1* Jeanette Fairhurst,1 Shamala Srinivas,2 William Hu,1 Boris Feld,1 Martin DiGrandi,3 Kevin Curran,3 Adma Ross,3 Jonathan D. Bloom,3 Marja van Zeijl,1 Thomas R. Jones,1 John O'Connell,1 and Jeffrey I. Cohen2

Infectious Diseases Section, Department of Molecular Biology/Virology,1 Department of Chemical Sciences, Wyeth Vaccines, Pearl River, New York 10965,3 Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 19 August 2002/ Accepted 14 November 2002

A series of nonnucleoside, N-{alpha}-methylbenzyl-N'-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.

* Corresponding author. Present address: Viral Vaccine Research, Wyeth, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-4709. Fax: (845) 602-4977. E-mail: visallr{at}wyeth.com.

Journal of Virology, February 2003, p. 2349-2358, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2349-2358.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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