A POTENT PEPTIDOMIMETIC INHIBITOR OF HSV RIBONUCLEOTIDE REDUCTASE WITH ANTIVIRAL ACTIVITY IN-VIVO

HERPES simplex viruses (HSV) types 1 and 2 encode their own ribonucleo tide reductases (RNRs) (EC 1.17.4.1) to convert ribonucleoside diphosp hates into the corresponding deoxyribonucleotides(1). Like other iron- dependent RNRs, the viral enzyme is formed by the reversible associati on of two distinct homodimeric subunits(2). The carboxy terminus of th e RNR small subunit (R2) is critical for subunit association(3,4) and synthetic peptides containing these amino-acid sequences selectively i nhibit the viral enzyme by preventing subunit association(4-9). Increa sing evidence indicates that the HSV RNR is important for virulence an d reactivation from latency(10-14). Previously, we reported on the des ign of HSV RNR inhibitors with enhanced inhibitory potency in vitro(4, 15,16). We now report on BILD 1263, which to our knowledge is the firs t HSV RNR subunit-association inhibitor with antiviral activity in viv o. This compound suppresses the replication of HSV-1, HSV-2 and acyclo vir-resistant HSV strains in cell culture, and also strongly potentiat es the antiviral activity of acyclovir. Most importantly, its anti-her petic activity is shown in a murine ocular model of HSV-1-induced kera titis, providing an example of potent nonsubstrate-based antiviral age nts that prevent protein-protein inter actions. The unique antiviral p roperties of BILD 1263 may lead to the design of new strategies to tre at herpesvirus infections in humans.