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Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.

Abstract

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.

Authors+Show Affiliations

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. Department of Pharmacy , Saarland University , Campus E8.1 , 66123 Saarbrücken , Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig , 66123 Saarbrücken , Germany.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. Department of Pharmacy , Saarland University , Campus E8.1 , 66123 Saarbrücken , Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig , 66123 Saarbrücken , Germany.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.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.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.German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig , 66123 Saarbrücken , Germany. Institute of Virology , Hannover Medical School , Carl-Neuberg-Strasse 1 , 30625 Hannover , Germany.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. Department of Pharmacy , Saarland University , Campus E8.1 , 66123 Saarbrücken , Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig , 66123 Saarbrücken , Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31944659

Citation

Kirsch, Philine, et al. "Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus." ACS Chemical Biology, 2020.
Kirsch P, Jakob V, Elgaher WAM, et al. Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus. ACS Chem Biol. 2020.
Kirsch, P., Jakob, V., Elgaher, W. A. M., Walt, C., Oberhausen, K., Schulz, T. F., & Empting, M. (2020). Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus. ACS Chemical Biology, doi:10.1021/acschembio.9b00845.
Kirsch P, et al. Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus. ACS Chem Biol. 2020 Jan 24; PubMed PMID: 31944659.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus. AU - Kirsch,Philine, AU - Jakob,Valentin, AU - Elgaher,Walid A M, AU - Walt,Christine, AU - Oberhausen,Kevin, AU - Schulz,Thomas F, AU - Empting,Martin, Y1 - 2020/01/24/ PY - 2020/1/17/pubmed PY - 2020/1/17/medline PY - 2020/1/17/entrez JF - ACS chemical biology JO - ACS Chem. Biol. N2 - 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. SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/31944659/Discovery_of_Novel_Latency-Associated_Nuclear_Antigen_Inhibitors_as_Antiviral_Agents_Against_Kaposi´s_Sarcoma-Associated_Herpesvirus L2 - https://dx.doi.org/10.1021/acschembio.9b00845 DB - PRIME DP - Unbound Medicine ER -