Abstract
HERPES simplex viruses (HSV) types 1 and 2 encode their own ribonucleotide reductases (RNRs) (EC 1.17.4.1) to convert ribo-nucleoside diphosphates into the corresponding deoxyribo-nucleotides1. Like other iron-dependent RNRs, the viral enzyme is formed by the reversible association of two distinct homodimeric subunits2. The carboxy terminus of the RNR small subunit (R2) is critical for subunit association3,4 and synthetic peptides containing these amino-acid sequences selectively inhibit the viral enzyme by preventing subunit association4–9. Increasing evidence indicates that the HSV RNR is important for virulence and reactivation from latency10–14. Previously, we reported on the design of HSV RNR inhibitors with enhanced inhibitory potency in vitro4,15,16. We now report on BILD 1263, which to our knowledge is the first HSV RNR subunit-association inhibitor with antiviral activity in vivo. This compound suppresses the replication of HSV-1, HSV-2 and acyclovir-resistant HSV strains in cell culture, and also strongly potentiates the antiviral activity of acyclovir. Most importantly, its anti-herpetic activity is shown in a murine ocular model of HSV-1-induced keratitis, providing an example of potent non-substrate-based antiviral agents that prevent protein–protein interactions. The unique antiviral properties of BILD 1263 may lead to the design of new strategies to treat herpesvirus infections in humans.
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Liuzzi, M., Déziel, R., Moss, N. et al. A potent peptidomimetic inhibitor of HSV ribonucleotide reductase with antiviral activity in vivo. Nature 372, 695–698 (1994). https://doi.org/10.1038/372695a0
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DOI: https://doi.org/10.1038/372695a0
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