The catalytic site of the
HIV integrase is contained within an
RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two
proteins with potential
RNase H-like folds, the infected cell
protein 8 (ICP8)
DNA-binding protein, which is necessary for
viral DNA replication and exhibits
recombinase activity in vitro, and the viral
terminase, which is essential for
viral DNA cleavage and packaging. Therefore, we hypothesized that
HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the
terminase. To test this, we evaluated the effect of 118-D-24, a potent
HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of
integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 µM, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 µM. XZ45 blocked HSV
viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8
recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of
Kaposi's sarcoma herpesvirus from
latent infection. Our results argue that inhibitors of
enzymes with
RNase H-like folds may represent a general
antiviral strategy, which is useful not only against HIV but also against herpesviruses. Importance: The herpesviruses cause considerable morbidity and mortality.
Nucleoside analogs have served as effective
antiviral agents against the herpesviruses, but resistance can arise through viral mutation. Second-line anti-herpes drugs have limitations in terms of pharmacokinetic properties and/or toxicity, so there is a great need for additional drugs for treatment of herpesviral
infections. This study showed that the
HIV integrase inhibitors also block herpesviral
infection, raising the important potential of a new class of anti-herpes drugs and the prospect of drugs that combat both HIV and the herpesviruses.