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

Kaposi's sarcoma-associatedherpesvirus (KSHV) can establishlatent lifelong infections in infected individuals. During viral latency,the latency-associated nuclear antigen (LANA) mediates the replicationof the latent viral genome in dividing cells and tethers them to mitoticchromosomes, thus ensuring their partitioning into daughter cellsduring mitosis. This study aims to inhibit Kaposi's sarcoma-associatedherpesvirus (KSHV) latent replication by targeting the LANA-DNAinteraction using small molecular entities. Drawing from first-generationinhibitors and using growth vectors identified through STD-NMR, weexpanded 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 mobilityshift assays (EMSA). Our most potent compounds successfully inhibitLANA-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 serveas qualified leads for the future refinement of small molecule inhibitorsof KSHV latent replication.

Automated summary

This study aims to inhibit Kaposi's sarcoma-associated herpesvirus (KSHV) latent replication by targeting the LANA-DNA interaction using small molecular entities. Through STD-NMR and cell-free tests via electrophoretic mobility shift assays (EMSA), the SAR of the compounds was better understood. The most potent compounds successfully inhibit LANA-mediated replication in cell-based assays and possess favorable in vitro ADMET-profiles.