{"_id":"aC2XkJyGY3js5Y7LS","bibbaseid":"anonymous-proteinphosphatase1targetingsmallmoleculec31inhibitsebolavirusreplication-2018","authorIDs":[],"bibdata":{"bibtype":"article","type":"article","author":[{"propositions":[],"lastnames":["Ammosova"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Pietzsch"],"firstnames":["C.A."],"suffixes":[]},{"propositions":[],"lastnames":["Saygideǧer"],"firstnames":["Y."],"suffixes":[]},{"propositions":[],"lastnames":["Ilatovsky"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Lin"],"firstnames":["X."],"suffixes":[]},{"propositions":[],"lastnames":["Ivanov"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Kumari"],"firstnames":["N."],"suffixes":[]},{"propositions":[],"lastnames":["Jerebtsova"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Kulkarni"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Petukhov"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Üren"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Bukreyev"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Nekhai"],"firstnames":["S."],"suffixes":[]}],"title":"Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication","journal":"Journal of Infectious Diseases","year":"2018","volume":"218","pages":"S627-S635","doi":"10.1093/infdis/jiy422","note":"cited By 2","url":"https://www.scopus.com/inward/record.uri?eid=2-s2.0-85057155054&doi=10.1093%2finfdis%2fjiy422&partnerID=40&md5=c58e2b99b91ae27b7515b1c810275bfc","affiliation":"Center for Sickle Cell Disease, Howard University, 2201 Georgia Ave., NW Washington, DC 20059, United States; Department of Medicine, Howard University, United States; Department of Microbiology, Howard University, United States; College of Pharmacy, Howard University, United States; Lombardi Comprehensive Cancer Center, Georgetown University, Washington, United States; Department of Pathology, University of Texas Medical Branch, Galveston, United States; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, United States; Galveston National Laboratory, University of Texas Medical Branch, Galveston, United States; Yakut Science Center for Complex Medical Problems, Yakutsk, Russian Federation; Division of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute, St. Petersburg, Russian Federation","abstract":"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. © 2018. This article contains public sector information licensed under the Open Government Licence v3.0.","author_keywords":"Ebola virus; protein phosphatase 1; transcription inhibitor.","funding_details":"National Institutes of Health1R01HL125005, U19AI109664, P30AI117970, 1P50HL118006, 5G12MD007597, P30CA51008","key":"Ammosova2018S627","id":"Ammosova2018S627","bibbaseid":"anonymous-proteinphosphatase1targetingsmallmoleculec31inhibitsebolavirusreplication-2018","role":"author","urls":{"Paper":"https://www.scopus.com/inward/record.uri?eid=2-s2.0-85057155054&doi=10.1093%2finfdis%2fjiy422&partnerID=40&md5=c58e2b99b91ae27b7515b1c810275bfc"},"metadata":{"authorlinks":{}},"downloads":0},"bibtype":"article","biburl":"https://bio.pnpi.nrcki.ru/wp-content/uploads/2019/12/lbm_2019_10.txt","creationDate":"2019-11-05T13:18:15.228Z","downloads":0,"keywords":[],"search_terms":["protein","phosphatase","targeting","small","molecule","c31","inhibits","ebola","virus","replication"],"title":"Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication","year":2018,"dataSources":["YYLjupmCazkNqWNEJ"]}