Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation: resistance maps to the UL6 gene.
In our search for novel inhibitors of herpes simplex virus type 1 (HSV-1), a new class of thiourea inhibitors was discovered. N-(4-[3-(5-Chloro-2,4-dimethoxyphenyl)-thioureido]-phenyl)-acetamide and its 2-fluoro-benzamide derivative inhibited HSV-1 replication. HSV-2, human cytomegalovirus, and varicella-zoster virus were inhibited to a lesser extent. The compounds acted late in the replication cycle by impairing both the cleavage of concatameric viral DNA into progeny genome length and the packaging of the DNA into capsids, indicative of a defect in the encapsidation process. To uncover the molecular target of the inhibition, resistant HSV-1 isolates were generated, and the mutation responsible for the resistance was mapped using marker transfer techniques. Each of three independent isolates had point mutations in the UL6 gene which resulted in independent single-amino-acid changes. One mutation was located in the N terminus of the protein (E121D), while two were located close together in the C terminus (A618V and Q621R). Each of these point mutations was sufficient to confer drug resistance when introduced into wild-type virus. The UL6 gene is one of the seven HSV-1 genes known to play a role in DNA packaging. This novel class of inhibitors has provided a new tool for dissection of HSV-1 encapsidation mechanisms and has uncovered a new viable target for the treatment of herpesviral diseases.
van Zeijl
M
M
Department of Molecular Biology/Virology, Wyeth-Ayerst Research, Pearl River, New York 10965, USA. vanzeim@war.wyeth.com
Fairhurst
J
J
Jones
T R
TR
Vernon
S K
SK
Morin
J
J
LaRocque
J
J
Feld
B
B
O'Hara
B
B
Bloom
J D
JD
Johann
S V
SV
D000818:Animals; D002213:Capsid; D036022:Capsid Proteins; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000187:drug effects*; D004352:Drug Resistance, Microbial; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D014709:Vero Cells; D014764:Viral Proteins; D014779:Virus Replication / Q000187:drug effects
D036022:Capsid Proteins; D004279:DNA, Viral; D014764:Viral Proteins; C069185:DNA cleavage and packaging proteins, Herpesvirus; D013890:Thiourea