Modulators of\nthe Hop-HSP90 Protein–Protein\nInteraction Disrupt KSHV Lytic Replication

The central role\nof the chaperome in maintaining cellular\nproteostasis\nhas seen numerous viral families evolve to parasitically exploit host\nchaperones in their life cycle. The HSP90 chaperone protein and its\ncochaperone Hop have both individually been shown to be essential\nfactors for Kaposi sarcoma-associated herpesvirus (KSHV) lytic replication.\nGiven the fundamental regulatory role that protein–protein\ninteractions (PPIs) play in cellular biology, we reasoned that disrupting\nthe Hop-HSP90 PPI may provide a new host-based target for inhibiting\nKSHV lytic replication. This study expands upon a previous report\nof non-natural peptides, which were found to disrupt the association\nbetween the Hop<sub>TPR2A</sub> domain and its interacting HSP90<sub>CTD</sub>. Here, in addition to providing insight into the structure–activity\nrelationships of PPI inhibition, we show disruption of the full-length\nHop-HSP90 PPI. The inhibitory peptides selectively engaged the Hop<sub>TPR2A</sub> domain in cell lysates and when tethered to a cell-penetrating\npeptide acted as noncytotoxic inhibitors of KSHV lytic replication\nby lowering the viral load, preventing the production of infectious\nvirions, and reducing the expression of KSHV lytic genes. In addition\nto tentative evidence of Hop-HSP90 PPI as a much-needed target for\nKSHV drug discovery, this study represents an important step in understanding\nviral interactions with the host proteostasis machinery.