2. Academic Validation
  3. Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery

Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery

  • Antimicrob Agents Chemother. 2020 Jun 23;64(7):e00649-20. doi: 10.1128/AAC.00649-20.
Rana Abdelnabi # 1,  Kristina Kovacikova # 2,  Julia Moesslacher 3,  Kim Donckers 1,  Verena Battisti 4,  Pieter Leyssen 1,  Thierry Langer 4,  Gerhard Puerstinger 3,  Gilles Quérat 5,  Changqing Li 6,  Etienne Decroly 6,  Ali Tas 2,  Arnaud Marchand 7,  Patrick Chaltin 7,  Bruno Coutard 5,  Martijn van Hemert 2,  Johan Neyts # 1,  Leen Delang # 8
Affiliations

Affiliations

  • 1 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
  • 2 Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.
  • 3 Department of Pharmaceutical Chemistry, University of Innsbruck, Innsbruck, Austria.
  • 4 University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria.
  • 5 Unité des Virus Emergents (UVE: Aix-Marseille University-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France.
  • 6 Aix Marseille University, CNRS, AFMB UMR7257, Marseille, France.
  • 7 Centre for Drug Design and Discovery, KU Leuven, Leuven, Belgium.
  • 8 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium [email protected].
  • # Contributed equally.
PMID: 32340991 DOI: 10.1128/AAC.00649-20
Abstract

Despite the worldwide reemergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or Antiviral treatment available. Here, we aimed to identify the target of a novel class of CHIKV inhibitors, i.e., the CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low-micromolar range. A CHVB-resistant variant (CHVBres) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2, and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ∼18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVBres was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.

Keywords

CHIKV; MADTP; antivirals; capping; chikungunya virus; nonstructural protein 1; nsP1.

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