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

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.

• Authors: Ying Wang, Sangwon Lee, Ya Ha, Wing Lam, Shao-Ru Chen, Ginger E Dutschman, Elizabeth A Gullen, Susan P Grill, Yao Cheng, Alois Fürstner, Samson Francis, David C Baker, Xiaoming Yang, Kuo-Hsiung Lee, Yung-Chi Cheng
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 10037 (08 30 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28855547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• DCB 3503
• HSC70 Heat-Shock Proteins
• Indolizines
• Phenanthrenes
• RNA, Viral
• tylophorine

Topics

• Alkaloids (chemistry, pharmacology)
• Allosteric Regulation
• Allosteric Site
• HSC70 Heat-Shock Proteins (chemistry, metabolism)
• Hepacivirus (physiology)
• Humans
• Indolizines (chemistry, pharmacology)
• Nucleotide Motifs
• Phenanthrenes (chemistry, pharmacology)
• Protein Binding
• RNA, Viral (chemistry, metabolism)
• Virus Replication (drug effects)