Targeted Protein Degradation of the Latency-Associated Nuclear Antigen Evicts Kaposi Sarcoma-Associated Herpesvirus Episomes From Infected Cells In Vitro

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV), a gamma-herpesvirus, is the main etiological agent of several tumors, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The large, double-stranded viral genome of KSHV is maintained as a latent episome in the nucleus of host cells, where a small subset of viral genes is expressed that facilitate evasion of immune responses and promotion of cell survival and proliferation supporting tumorigenesis. The major latency-associated nuclear antigen (LANA) is an essential viral factor that is required for genome replication and segregation to maintain viral genomes within dividing cells. Given the essential role of LANA to maintain viral latency, efforts have focused on targeting LANA's role in replication and segregation as a mechanism to overcome latency and tumorigenesis. However, given the complexity in small molecule targeting to DNA-binding domains, current efforts focused on drugging LANA continue to reach potency milestones for clinical trials. Here, we developed a HaloTag-based PROTAC model as a proof-of-concept for targeted LANA protein degradation. Our findings highlight the power of a PROTAC-based strategy on eliminating LANA and viral persistence in tissue culture demonstrating promise in the on-going challenge for targeting this major viral factor in KSHV latency.

Keywords: Kaposi's sarcoma‐associated herpesvirus; LANA; PROTAC; targeted protein degradation; viral latency.