Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus
| Autor: | Walid A. M. Elgaher, Christine Walt, Thomas F. Schulz, Kevin Oberhausen, Valentin Jakob, Martin Empting, Philine Kirsch |
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| Přispěvatelé: | HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
viruses Microbial Sensitivity Tests medicine.disease_cause 01 natural sciences Biochemistry Antiviral Agents Small Molecule Libraries 03 medical and health sciences Antigen Drug Discovery medicine Humans Kaposi's sarcoma-associated herpesvirus Antigens Viral Latency-associated nuclear antigen 010405 organic chemistry business.industry virus diseases Nuclear Proteins General Medicine DNA Hep G2 Cells biochemical phenomena metabolism and nutrition medicine.disease Virology 0104 chemical sciences 030104 developmental biology HEK293 Cells Herpesvirus 8 Human Molecular Medicine Sarcoma business Protein Binding |
| Zdroj: | ACS chemical biology |
| ISSN: | 1554-8937 |
| Popis: | With the aim to develop novel antiviral agents against Kaposi's Sarcoma Herpesvirus (KSHV), we are targeting the latency-associated nuclear antigen (LANA). This protein plays an important role in viral genome maintenance during latent infection. LANA has the ability to tether the viral genome to the host nucleosomes and, thus, ensures latent persistence of the viral genome in the host cells. By inhibition of the LANA-DNA interaction, we seek to eliminate or reduce the load of the viral DNA in the host. To achieve this goal, we screened our in-house library using a dedicated fluorescence polarization (FP)-based competition assay, which allows for the quantification of LANA-DNA-interaction inhibition by small organic molecules. We successfully identified three different compound classes capable of disrupting this protein-nucleic acid interaction. We characterized these compounds by IC50 dose-response evaluation and confirmed the compound-LANA interaction using surface plasmon resonance (SPR) spectroscopy. Furthermore, two of the three hit scaffolds showed only marginal cytotoxicity in two human cell lines. Finally, we conducted STD-NMR competition experiments with our new hit compounds and a previously described fragment-sized inhibitor. Based on these results, future compound linking approaches could serve as a promising strategy for further optimization studies in order to generate highly potent KSHV inhibitors. |
| Databáze: | OpenAIRE |
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