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J Med Chem. 2019 Apr 25;62(8):3924-3939. doi: 10.1021/acs.jmedchem.8b01827. Epub 2019 Apr 12.

Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8.

Author information

1
Department of Drug Design and Optimization (DDOP) , Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI) , Campus E8.1 , 66123 Saarbrücken , Germany.
2
Department of Pharmacy , Saarland University , Campus E8.1 , 66123 Saarbrücken , Germany.
3
German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig , 66123 Saarbrücken , Germany.
4
Institute of Virology , Hannover Medical School , Carl-Neuberg-Strasse 1 , 30625 Hannover , Germany.

Abstract

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.

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