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Titel: Disrupting Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor
VerfasserIn: Berwanger, Aylin
Stein, Saskia C.
Kany, Andreas M.
Gartner, Melissa
Loretz, Brigitta
Lehr, Claus-Michael
Hirsch, Anna
Schulz, Thomas F.
Empting, Martin
Sprache: Englisch
Titel: Journal of medicinal chemistry
Bandnummer: 66
Heft: 15
Seiten: 10782-10790
Verlag/Plattform: ACS
Erscheinungsjahr: 2023
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
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.
DOI der Erstveröffentlichung: 10.1021/acs.jmedchem.3c00990
URL der Erstveröffentlichung: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00990
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-434249
hdl:20.500.11880/38933
http://dx.doi.org/10.22028/D291-43424
ISSN: 1520-4804
0095-9065
Datum des Eintrags: 11-Nov-2024
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Pharmazie
Professur: NT - Prof. Dr. Anna Hirsch
NT - Prof. Dr. Claus-Michael Lehr
NT - Keiner Professur zugeordnet
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes



Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons