Modulators of the Hop-HSP90 Protein-Protein Interaction Disrupt Early-Stage of KSHV Lytic Replication

The central role of the chaperome in maintaining cellular proteostasis has seen numerous viral families evolve to parasitically exploit host chaperones in their life cycle. The HSP90 chaperone protein and its co-chaperone Hop, have both individually been shown to be essential factors for KSHV lytic replication. Given the fundamental regulatory role that PPIs play in cellular biology, we reasoned that disrupting the Hop-HSP90 PPI may provide a new host-based target for inhibiting KSHV lytic replication. This study expands upon a previous report of non-natural peptides, which disrupted the association between the HopTPR2A and its interacting HSP90CTD. Here, in addition to demonstrating disruption of the full-length Hop-HSP90PPI, and selective engagement with the HopTPR2A domain in cell lysates, we showed that a cell-penetrating peptide modified analogue, inhibited intracellular HSP90 and acted as a non-cytotoxic inhibitor of early-stage KSHV lytic replication. Importantly, this activity resulted from inhibition of specific KSHV lytic genes, rather than a global reduction in viral DNA transcription. In addition to tentative evidence for the Hop-HSP90 PPI as a much-needed target for KSHV drug discovery, this study represents an important step in understanding host HSP90 – viral interactions.