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dc.contributor.authorKirsch, Philine
dc.contributor.authorJakob, Valentin
dc.contributor.authorOberhausen, Kevin
dc.contributor.authorStein, Saskia C
dc.contributor.authorCucarro, Ivano
dc.contributor.authorSchulz, Thomas F
dc.contributor.authorEmpting, Martin
dc.date.accessioned2019-07-05T14:38:50Z
dc.date.available2019-07-05T14:38:50Z
dc.date.issued2019-04-25
dc.identifier.citationJ Med Chem. 2019 Apr 25;62(8):3924-3939. doi: 10.1021/acs.jmedchem.8b01827. Epub 2019 Apr 12.en_US
dc.identifier.issn1520-4804
dc.identifier.pmid30888817
dc.identifier.doi10.1021/acs.jmedchem.8b01827
dc.identifier.urihttp://hdl.handle.net/10033/621849
dc.description.abstractThe latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.en_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleFragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalJournal of Medicinal Chemistryen_US
dc.source.journaltitleJournal of medicinal chemistry


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