Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8.
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Authors
Kirsch, PhilineJakob, Valentin
Oberhausen, Kevin
Stein, Saskia C
Cucarro, Ivano
Schulz, Thomas F
Empting, Martin

Issue Date
2019-04-25
Metadata
Show full item recordAbstract
The 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.Citation
J Med Chem. 2019 Apr 25;62(8):3924-3939. doi: 10.1021/acs.jmedchem.8b01827. Epub 2019 Apr 12.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
American Chemical SocietyJournal
Journal of Medicinal ChemistryPubMed ID
30888817Type
ArticleLanguage
enISSN
1520-4804ae974a485f413a2113503eed53cd6c53
10.1021/acs.jmedchem.8b01827
Scopus Count
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- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
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