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Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.
Stevaert, Annelies; Krasniqi, Besir; Van Loy, Benjamin; Nguyen, Tien; Thomas, Joice; Vandeput, Julie; Jochmans, Dirk; Thiel, Volker; Dijkman, Ronald; Dehaen, Wim; Voet, Arnout; Naesens, Lieve.
  • Stevaert A; Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • Krasniqi B; Molecular Design and Synthesis, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium.
  • Van Loy B; Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • Nguyen T; Biochemistry, Molecular and Structural Biology, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium.
  • Thomas J; Molecular Design and Synthesis, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium.
  • Vandeput J; Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • Jochmans D; Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
  • Thiel V; Institute of Virology and Immunology (IVI), 3012 Bern and 3012 Bern, Switzerland.
  • Dijkman R; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
  • Dehaen W; Institute of Virology and Immunology (IVI), 3012 Bern and 3012 Bern, Switzerland.
  • Voet A; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
  • Naesens L; Institute for Infectious Diseases (IFIK), University of Bern, 3012 Bern, Switzerland.
J Med Chem ; 64(9): 5632-5644, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1193564
Semantic information from SemMedBD (by NLM)
1. betulonic acid INTERACTS_WITH Endoribonucleases
Subject
betulonic acid
Predicate
INTERACTS_WITH
Object
Endoribonucleases
2. betulonic acid INTERACTS_WITH Endoribonucleases
Subject
betulonic acid
Predicate
INTERACTS_WITH
Object
Endoribonucleases
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Oleanolic Acid / Antiviral Agents / Virus Replication / Viral Nonstructural Proteins / Coronavirus 229E, Human / Endoribonucleases / Enzyme Inhibitors Type of study: Prognostic study Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.0c02124

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Oleanolic Acid / Antiviral Agents / Virus Replication / Viral Nonstructural Proteins / Coronavirus 229E, Human / Endoribonucleases / Enzyme Inhibitors Type of study: Prognostic study Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.0c02124