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dc.contributor.authorKirsch, Philine
dc.contributor.authorStein, Saskia C
dc.contributor.authorBerwanger, Aylin
dc.contributor.authorRinkes, Julia
dc.contributor.authorJakob, Valentin
dc.contributor.authorSchulz, Thomas F
dc.contributor.authorEmpting, Martin
dc.date.accessioned2020-07-22T14:03:12Z
dc.date.available2020-07-22T14:03:12Z
dc.date.issued2020-06-28
dc.identifier.citationEur J Med Chem. 2020;202:112525. doi:10.1016/j.ejmech.2020.112525.en_US
dc.identifier.pmid32634628
dc.identifier.doi10.1016/j.ejmech.2020.112525
dc.identifier.urihttp://hdl.handle.net/10033/622356
dc.description.abstractThe Latency-associated nuclear antigen (LANA) plays a central role for the latent persistence of the Kaposi's Sarcoma Herpesvirus (KSHV) in the human host and helps to establish lifelong infections. Herein, we report our efforts towards hit-to-lead generation starting from a previously discovered LANA-DNA inhibitor. By tethering the viral genome to the host nucleosomes, LANA ensures the segregation and persistence of the viral DNA during mitosis. LANA is also required for the replication of the latent viral episome during the S phase of the cell cycle. We aim to inhibit the interaction between LANA and the viral genome to prevent the latent persistence of KSHV in the host organism. Medicinal chemistry-driven optimization studies and structure-activity-relationship investigation led to the discovery of an improved LANA inhibitor. The functional activity of our compounds was evaluated using a fluorescence polarization (FP)-based interaction inhibition assay and electrophoretic mobility shift assay (EMSA). Even though a crystal structure of the ligand protein complex was not available, we successfully conducted hit optimization toward a low micromolar protein-nucleic acid-interaction inhibitor. Additionally, we applied STD-NMR studies to corroborate target binding and to gain insights into the binding orientation of our most potent inhibitor, providing opportunities for further rational design of more efficient LANA-targeting anti KSHV agents in future studies.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectCuAACen_US
dc.subjectElectrophoretic mobility shift assay (EMSA)en_US
dc.subjectFluorescence polarization (FP)-Based interaction inhibition assayen_US
dc.subjectHit-to-lead optimizationen_US
dc.subjectKaposi’s sarcoma herpesvirus (KSHV)en_US
dc.subjectLatency-associated nuclear antigen (LANA)en_US
dc.subjectSTD-NMRen_US
dc.titleHit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi's sarcoma-associated herpesvirus infections.en_US
dc.typeArticleen_US
dc.identifier.eissn1768-3254
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalEuropean journal of medicinal chemistryen_US
dc.source.volume202
dc.source.beginpage112525
dc.source.endpage
refterms.dateFOA2020-07-22T14:03:13Z
dc.source.journaltitleEuropean journal of medicinal chemistry
dc.source.countryFrance


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