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Disrupting Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2023 Aug 10; Vol. 66 (15), pp. 10782-10790. Date of Electronic Publication: 2023 Jul 28. - Publication Year :
- 2023
-
Abstract
- 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.
- Subjects :
- Humans
Caco-2 Cells
Virus Replication
Virus Latency
Herpesvirus 8, Human metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 66
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 37506283
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c00990