Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication

J Infect Dis. 2018 Nov 22;218(suppl_5):S627-S635. doi: 10.1093/infdis/jiy422.

Abstract

Background: Ebola virus (EBOV) infection causes severe hemorrhagic fever. EBOV transcription is controlled by host protein phosphatase 1 (PP1), which dephosphorylates VP30 protein. We previously developed 1E7-03, a compound targeting a noncatalytic site of PP1 that induced VP30 phosphorylation and inhibited EBOV transcription. Here, we attempted to further improve 1E7-03, which was not stable in murine serum.

Results: High-throughput screening with EBOV-green fluorescent protein was conducted on 72 1E7-03 analogs and identified 6 best inhibitory and the least toxic compounds. A parallel in silico screening of compounds from the ZINC database by docking to PP1 identified the best-binding compound C31, which was also present among the top 6 compounds found in the viral screen. C31 showed the best EBOV inhibitory activity among the top 6 compounds and also inhibited EBOV minigenome. C31 bound to the PP1 C-terminal groove in vitro and increased VP30 phosphorylation in cultured cells. C31 demonstrated improved stability in mouse plasma and cell permeability, compared with 1E7-03. It was also detected for 24 hours after injection in mice.

Conclusion: C31 represents a novel PP1-targeting EBOV inhibitor with improved pharmacological properties that can be further evaluated for future antifiloviral therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Catalytic Domain
  • Drug Stability
  • Ebolavirus / drug effects*
  • Ebolavirus / physiology
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Phosphorylation
  • Protein Phosphatase 1 / chemistry
  • Protein Phosphatase 1 / metabolism*
  • Transcription Factors / metabolism
  • Viral Proteins / metabolism
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Transcription Factors
  • VP30 protein, ebola virus
  • Viral Proteins
  • Protein Phosphatase 1