Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
| Autor: | Saskia C. Stein, Valentin Jakob, Martin Empting, Philine Kirsch, Kevin Oberhausen, Thomas F. Schulz, Ivano Cucarro |
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| Přispěvatelé: | HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. |
| Rok vydání: | 2019 |
| Předmět: |
viruses
medicine.disease_cause 01 natural sciences Antiviral Agents 03 medical and health sciences Structure-Activity Relationship Antigen Drug Discovery medicine Humans Kaposi's sarcoma-associated herpesvirus Antigens Viral Sarcoma Kaposi 030304 developmental biology Latency-associated nuclear antigen 0303 health sciences Binding Sites Chemistry Imidazoles virus diseases Nuclear Proteins Virology 0104 chemical sciences Protein Structure Tertiary Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Herpesvirus 8 Human Tetherin Molecular Medicine Human herpesvirus Protein Binding |
| Zdroj: | Journal of medicinal chemistry |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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