Toward Anti‐Herpesviral PROTACs: Assessing the Challenges for Targeted Protein Degradation on the Example of Kaposi's Sarcoma‐Associated Herpesvirus Latency‐Associated Nuclear Antigen

Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-herpesvirus linked to several malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Among its numerous encoded proteins, the latency-associated nuclear antigen (LANA) plays a pivotal role in the maintenance of viral latency and oncogenesis. This manuscript focuses on therapeutic strategies aimed at targeting LANA to prevent KSHV-associated diseases. Following the concept of proteolysis-targeting chimeras (PROTACs), heterobifunctional compounds are designed and synthesized, which are able to bind LANA as well as specific E3 ligases. To achieve induction of targeted protein degradation, formation of functional ternary complexes as well as uptake into cells is required, which necessitates optimization of multiple compound parameters in parallel. Hence, the conjugates are tested using an assay pipeline tailored for PROTAC drug discovery by checking properties such as binding affinities, formation of ternary complexes, and in vitro absorption, distribution, metabolism, excretion (ADME) data. Restricted permeation as the reason for lack of intracellular target degradation is especially identified.