Identification of small molecule compounds that selectively inhibit varicella-zoster virus replication.
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.
Visalli
Robert J
RJ
Infectious Diseases Section, Department of Molecular Biology/Virology, Wyeth Vaccines, Pearl River, NY 1096, USA. visallr@wyeth.com
Fairhurst
Jeanette
J
Srinivas
Shamala
S
Hu
William
W
Feld
Boris
B
DiGrandi
Martin
M
Curran
Kevin
K
Ross
Adma
A
Bloom
Jonathan D
JD
van Zeijl
Marja
M
Jones
Thomas R
TR
O'Connell
John
J
Cohen
Jeffrey I
JI
D000212:Acyclovir / Q000494:pharmacology; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002213:Capsid / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
C472011:2-fluoro-N-(4-(3-(1-(4-fluorophenyl)ethyl)thioureido)phenyl)benzamide; D000998:Antiviral Agents; D001549:Benzamides; C472012:N-(2-cyano-4-(3-(1-(4-fluorophenyl)ethyl)thioureido)phenyl)-2-fluorobenzamide; D014764:Viral Proteins; C472013:isoquinoline-1-carboxylic acid (4-(3-(1-benzofuran-2-ylethyl)thioureido)phenyl)amide; D013890:Thiourea; D000212:Acyclovir