Novel Pyrrole–Imidazole Polyamide Hoechst Conjugate Suppresses Epstein–Barr Virus Replication and Virus-Positive Tumor Growth

Epstein–Barr virus (EBV) establishes
latent infection and
is associated with several types of lymphomas and carcinomas. EBV
nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells.
EBNA1 binds to the origin of virus plasmid replication (OriP) on the
EBV episome to initiate virus DNA replication and regulates virus
gene expression as a transcriptional activator. In this study, we
designed and synthesized a pyrrole–imidazole polyamide–Hoechst
33258 conjugate named EIP-2 (2), which specifically binds
to the OriP region with high affinity, to interrupt EBNA1-OriP binding
in vitro and in vivo. By eradicating the EBV episome in EBV-positive
cells, compound 2 selectively inhibited EBV-positive
cell proliferation. Moreover, the injection of 2 significantly
suppressed tumor growth in the mice xenograft tumor model. These findings
demonstrate that compound 2 is a potential therapeutic
candidate for the treatment of EBV-associated tumors.