Inhibitors of Kaposi???s Sarcoma Herpesvirus

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DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi's sarcoma and primary effusion lymphoma. KSHV latently infects tumor cells. In latent infection, the viral genome persists in tumor cells as a multiple copy, extrachromosomal plasmid (episome). To persist, the viral genome must replicate with each cell division and then segregate to daughter cell nuclei. KSHV latency-associated nuclear antigen (LANA) ensures these tasks are performed and that efficient transfer of the viral DNA to progeny tumor cells occurs. LANA tethers KSHV DNA to mitotic chromosomes to allow efficient segregation of viral episomes to daughter cell nuclei. C-terminal LANA self-associates to bind specific DNA sequence in the KSHV terminal repeat (TR) elements. This C-terminal LANA DNA binding is essential for KSHV DNA replication, tethering to mitotic chromosomes, and episome persistence. Currently, there are no small molecule inhibitors for LANA. Since LANA is critical for KSHV latent infection, chemical probes which block the essential LANA binding to the TR DNA would serve as extremely useful reagents to investigate LANA and KSHV biology. Such inhibitory small molecules would be of potential therapeutic benefit since tumor cell persistence is dependent on KSHV infection. This work will develop a robust, reproducible, and miniaturized fluorescence polarization (FP) assay for a high throughput screen for small molecules that inhibit KSHV LANA binding to its DNA recognition sequence. Pilot screens using the FP assay will validate the assay prior to high throughput screening. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma-associated herpesvirus has a causative role in certain human cancers. This work will develop tests to identify compounds that can be used to study this virus. These compounds may potentially be used to prevent and treat the cancers this virus causes.