2. Academic Validation
  3. Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z