2. Academic Validation
  3. Disrupting Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor

Disrupting Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Latent Replication with a Small Molecule Inhibitor

  • J Med Chem. 2023 Aug 10;66(15):10782-10790. doi: 10.1021/acs.jmedchem.3c00990.
Aylin Berwanger 1 2 3,  Saskia C Stein 3 4 5,  Andreas M Kany 1,  Melissa Gartner 2,  Brigitta Loretz 1,  Claus-Michael Lehr 1 2,  Anna K H Hirsch 1 2 5,  Thomas F Schulz 3 4 5,  Martin Empting 1 2 3 5
Affiliations

Affiliations

  • 1 Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), 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-Str. 1, 30625 Hannover, Germany.
  • 5 Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
PMID: 37506283 DOI: 10.1021/acs.jmedchem.3c00990
Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) can establish latent lifelong infections in infected individuals. During viral latency, the latency-associated nuclear antigen (LANA) mediates the replication of the latent viral genome in dividing cells and tethers them to mitotic chromosomes, thus ensuring their partitioning into daughter cells during mitosis. This study aims to inhibit Kaposi's sarcoma-associated herpesvirus (KSHV) latent replication by targeting the LANA-DNA interaction using small molecular entities. Drawing from first-generation inhibitors and using growth vectors identified through STD-NMR, we expanded these compounds using Suzuki-Miyaura cross-coupling. This led to a deeper understanding of SAR achieved by microscale thermophoresis (MST) measurements and cell-free tests via electrophoretic mobility shift assays (EMSA). Our most potent compounds successfully inhibit LANA-mediated replication in cell-based assays and demonstrate favorable in vitro ADMET-profiles, including suitable metabolic stability, Caco-2 permeability, and cytotoxicity. These compounds could serve as qualified leads for the future refinement of small molecule inhibitors of KSHV latent replication.

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