2. Academic Validation
  3. Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease

Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease

  • J Med Chem. 2021 May 13;64(9):5632-5644. doi: 10.1021/acs.jmedchem.0c02124.
Annelies Stevaert 1,  Besir Krasniqi 2,  Benjamin Van Loy 1,  Tien Nguyen 3,  Joice Thomas 2,  Julie Vandeput 1,  Dirk Jochmans 1,  Volker Thiel 4 5,  Ronald Dijkman 4 5 6,  Wim Dehaen 2,  Arnout Voet 3,  Lieve Naesens 1
Affiliations

Affiliations

  • 1 Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • 2 Molecular Design and Synthesis, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium.
  • 3 Biochemistry, Molecular and Structural Biology, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium.
  • 4 Institute of Virology and Immunology (IVI), 3012 Bern and 3012 Bern, Switzerland.
  • 5 Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
  • 6 Institute for Infectious Diseases (IFIK), University of Bern, 3012 Bern, Switzerland.
PMID: 33877845 DOI: 10.1021/acs.jmedchem.0c02124
Abstract

To develop Antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (Antiviral EC50: 0.6 μM) of HCoV-229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of HCoV-229E nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

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