9-Aminoacridine-based agents impair the bovine viral diarrhea virus (BVDV) replication targeting the RNA-dependent RNA polymerase (RdRp)

Bioorg Med Chem. 2018 Feb 15;26(4):855-868. doi: 10.1016/j.bmc.2018.01.001. Epub 2018 Jan 4.

Abstract

Bovine viral diarrhea virus (BVDV) infection is still a plague that causes important livestock pandemics. Despite the availability of vaccines against BVDV, and the implementation of massive eradication or control programs, this virus still constitutes a serious agronomic burden. Therefore, the alternative approach to combat Pestivirus infections, based on the development of antiviral agents that specifically inhibit the replication of these viruses, is of preeminent actuality and importance. Capitalizing from a long-standing experience in antiviral drug design and development, in this work we present and characterize a series of small molecules based on the 9-aminoacridine scaffold that exhibit potent anti-BVDV activity coupled with low cytotoxicity. The relevant viral protein target - the RNA-dependent RNA polymerase - the binding mode, and the mechanism of action of these new antivirals have been determined by a combination of in vitro (i.e., enzymatic inhibition, isothermal titration calorimetry and site-directed mutagenesis assays) and computational experiments. The overall results obtained confirm that these acridine-based derivatives are promising compounds in the treatment of BVDV infections and, based on the reported structure-activity relationship, can be selected as a starting point for the design of a new generation of improved, safe and selective anti-BVDV agents.

Keywords: 9-Aminoacridine derivatives; Anti-BVDV activity; Computational studies; Isothermal titration calorimetry; RNA polymerase inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminacrine / chemistry*
  • Aminacrine / metabolism
  • Aminacrine / pharmacology
  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Calorimetry
  • Cattle
  • Diarrhea Viruses, Bovine Viral / enzymology
  • Diarrhea Viruses, Bovine Viral / physiology*
  • Drug Design
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / genetics
  • RNA-Dependent RNA Polymerase / metabolism
  • Structure-Activity Relationship
  • Thermodynamics
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Aminacrine
  • RNA-Dependent RNA Polymerase