Hit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi’s sarcoma-associated herpesvirus infections
| Autor: | Saskia C. Stein, Julia Rinkes, Valentin Jakob, Martin Empting, Philine Kirsch, Thomas F. Schulz, Aylin Berwanger |
|---|---|
| Přispěvatelé: | HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. |
| Rok vydání: | 2020 |
| Předmět: |
viruses
Microbial Sensitivity Tests medicine.disease_cause Antiviral Agents 01 natural sciences Genome Structure-Activity Relationship 03 medical and health sciences Antigen Drug Discovery medicine Kaposi’s sarcoma herpesvirus (KSHV) Electrophoretic mobility shift assay Kaposi's sarcoma-associated herpesvirus Antigens Viral Mitosis S phase Fluorescence polarization (FP)-Based interaction inhibition assay 030304 developmental biology Pharmacology Latency-associated nuclear antigen (LANA) 0303 health sciences STD-NMR Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Nuclear Proteins virus diseases Herpesviridae Infections General Medicine Hit to lead Triazoles biochemical phenomena metabolism and nutrition Isoquinolines Ligand (biochemistry) Virology 0104 chemical sciences Hit-to-lead optimization DNA Viral Herpesvirus 8 Human Electrophoretic mobility shift assay (EMSA) CuAAC |
| Zdroj: | European journal of medicinal chemistry France |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2020.112525 |
| Popis: | The Latency-associated nuclear antigen (LANA) plays a central role for the latent persistence of the Kaposi's Sarcoma Herpesvirus (KSHV) in the human host and helps to establish lifelong infections. Herein, we report our efforts towards hit-to-lead generation starting from a previously discovered LANA-DNA inhibitor. By tethering the viral genome to the host nucleosomes, LANA ensures the segregation and persistence of the viral DNA during mitosis. LANA is also required for the replication of the latent viral episome during the S phase of the cell cycle. We aim to inhibit the interaction between LANA and the viral genome to prevent the latent persistence of KSHV in the host organism. Medicinal chemistry-driven optimization studies and structure-activity-relationship investigation led to the discovery of an improved LANA inhibitor. The functional activity of our compounds was evaluated using a fluorescence polarization (FP)-based interaction inhibition assay and electrophoretic mobility shift assay (EMSA). Even though a crystal structure of the ligand protein complex was not available, we successfully conducted hit optimization toward a low micromolar protein-nucleic acid-interaction inhibitor. Additionally, we applied STD-NMR studies to corroborate target binding and to gain insights into the binding orientation of our most potent inhibitor, providing opportunities for further rational design of more efficient LANA-targeting anti KSHV agents in future studies. |
| Databáze: | OpenAIRE |
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