Disrupting Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor

Kaposi’s sarcoma-associated
herpesvirus (KSHV) can establish
latent lifelong infections in infected individuals. During viral latency,
the latency-associated nuclear antigen (LANA) mediates the replication
of the latent viral genome in dividing cells and tethers them to mitotic
chromosomes, thus ensuring their partitioning into daughter cells
during mitosis. This study aims to inhibit Kaposi’s sarcoma-associated
herpesvirus (KSHV) latent replication by targeting the LANA–DNA
interaction using small molecular entities. Drawing from first-generation
inhibitors and using growth vectors identified through STD-NMR, we
expanded these compounds using Suzuki–Miyaura cross-coupling.
This led to a deeper understanding of SAR achieved by microscale thermophoresis
(MST) measurements and cell-free tests via electrophoretic mobility
shift assays (EMSA). Our most potent compounds successfully inhibit
LANA-mediated replication in cell-based assays and demonstrate favorable in vitro ADMET-profiles, including suitable metabolic stability,
Caco-2 permeability, and cytotoxicity. These compounds could serve
as qualified leads for the future refinement of small molecule inhibitors
of KSHV latent replication.