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.
Tatiana Ammosova  1  2  3 ,  Colette A Pietzsch  4  5  6 ,  Yasemin Saygideger  7 ,  Andrey Ilatovsky  8 ,  Xionghao Lin  1 ,  Andrey Ivanov  1 ,  Namita Kumari  1  2 ,  Marina Jerebtsova  9 ,  Amol Kulkarni  10 ,  Michael Petukhov  8 ,  Aykut Üren  7 ,  Alexander Bukreyev  4  5  6 ,  Sergei Nekhai  1  2  9
Affiliations
  • 1. Center for Sickle Cell Disease, Howard University.
  • 2. Department of Medicine, Howard University.
  • 3. Yakut Science Center for Complex Medical Problems, Yakutsk.
  • 4. Department of Pathology, University of Texas Medical Branch at Galveston.
  • 5. Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston.
  • 6. Galveston National Laboratory, University of Texas Medical Branch at Galveston.
  • 7. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D. C.
  • 8. Division of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
  • 9. Department of Microbiology, Howard University.
  • 10. College of Pharmacy, Howard University.
PMID: 30169869 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.

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