Tatiana Ammosova1,2,3, Colette A Pietzsch4,5,6, Yasemin Saygideger7, Andrey Ilatovsky8, Xionghao Lin1, Andrey Ivanov1, Namita Kumari1,2, Marina Jerebtsova9, Amol Kulkarni10, Michael Petukhov8, Aykut Üren7, Alexander Bukreyev4,5,6, Sergei Nekhai1,2,9. 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.
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.
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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