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Sci Rep. 2017 Aug 30;7(1):10037. doi: 10.1038/s41598-017-08815-z.

Tylophorine Analogs Allosterically Regulates Heat Shock Cognate Protein 70 And Inhibits Hepatitis C Virus Replication.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA. emilyywang@umac.mo.
2
Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, SAR, China. emilyywang@umac.mo.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
4
Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, SAR, China.
5
Max-Planck-Institut für Kohlenforschung, 45470, Mülheim/Ruhr, Germany.
6
Department of Chemistry, The University of Tennessee, Knoxville, TN, 37996, USA.
7
Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
8
Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
9
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA. yccheng@yale.edu.

Abstract

Tylophorine analogs have been shown to exhibit diverse activities against cancer, inflammation, arthritis, and lupus in vivo. In this study, we demonstrated that two tylophorine analogs, DCB-3503 and rac-cryptopleurine, exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype 1b Con 1 isolate. The inhibition of HCV replication is at least partially mediated through cellular heat shock cognate protein 70 (Hsc70). Hsc70 associates with the HCV replication complex by primarily binding to the poly U/UC motifs in HCV RNA. The interaction of DCB-3503 and rac-cryptopleurine with Hsc70 promotes the ATP hydrolysis activity of Hsc70 in the presence of the 3' poly U/UC motif of HCV RNA. Regulating the ATPase activity of Hsc70 may be one of the mechanisms by which tylophorine analogs inhibit HCV replication. This study demonstrates the novel anti-HCV activity of tylophorine analogs. Our results also highlight the importance of Hsc70 in HCV replication.

PMID:
28855547
PMCID:
PMC5577180
DOI:
10.1038/s41598-017-08815-z
[Indexed for MEDLINE]
Free PMC Article

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