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Inhibition of herpes simplex virus 1 gene expression by designer zinc-finger transcription factors

By Monika Papworth, Michael Moore, Mark Isalan, Michal Minczuk, Yen Choo and Aaron Klug


The herpes simplex virus 1 (HSV-1) replicative cycle begins by binding of the viral activator, VP16, to a set of sequences in the immediate-early (IE) gene promoters. With the aim of inhibiting this cycle, we have constructed a number of synthetic zinc-finger DNA-binding peptides by using recently reported methods. Peptides containing either three or six fingers, targeted to a viral promoter, were engineered as fusions with a KOX-1 transcription repression domain. These proteins bound to the HSV-1 IE175k (ICP4) promoter, in vitro, with nanomolar or subnanomolar binding affinity. However, in a chloramphenicol acetyltransferase reporter system, only the six-finger protein was found to repress VP16-activated transcription significantly. Thus the longer array of zinc fingers is required to compete successfully against VP16, one of the most powerful natural activators known. We found that the HSV-1 replication cycle can be partially repressed by the six-finger peptide with the viral titer reduced by 90%

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 2003
DOI identifier: 10.1073/pnas.252773399
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Provided by: PubMed Central
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