N-Substituted Benzyl Matrinic Acid Derivatives Inhibit Hepatitis C Virus (HCV) Replication through Down-Regulating Host Heat-Stress Cognate 70 (Hsc70) Expression

Du, Ning; Peng, Zong–Gen; Bi, Caifeng; Tang, Sheng; Li, Yinghong; Li, Jianrui; Zhu, Yanping; Zhang, Jingpu; Wang, Yan-Xiang; Jiang, Jian‐Dong; Song, Dan–Qing

doi:10.1371/journal.pone.0058675

Cited by 19 publications

(24 citation statements)

References 21 publications

(31 reference statements)

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“…YM-01, JG-40, JG-98 and JG-258 were synthesised and characterised as reported previously [20] and were dissolved in dimethyl sulphoxide (DMSO). Purity was >95% by nuclear magnetic resonance (NMR) and high-performance liquid chromatography (HPLC).…”

Section: Methodsmentioning

confidence: 99%

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Khachatoorian

Riahi

Ganapathy

et al. 2016

International Journal of Antimicrobial Agents

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The human molecular chaperones heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70) bind to the hepatitis C viral nonstructural protein 5A (NS5A) and regulate its activity. Specifically, Hsp70 is involved in NS5A-augmented internal ribosomal entry site (IRES)-mediated translation of the viral genome, whilst Hsc70 appears to be primarily important for intracellular infectious virion assembly. To better understand the importance of these two chaperones in the viral life cycle, infected human cells were treated with allosteric Hsp70/Hsc70 inhibitors (AHIs). Treatment with AHIs significantly reduced the production of intracellular virus at concentrations that were non-toxic to human hepatoma Huh7.5 cells. The supernatant of treated cultures was then used to infect naïve cells, revealing that AHIs also lowered levels of secreted virus. In contrast to their effects on virion assembly, AHIs did not impact the stability of NS5A or viral protein translation in IRES assays. These results suggest that Hsc70 plays a particularly important and sensitive role in virion assembly. Indeed, it was found that combination of AHIs with a peptide-based viral translation inhibitor exhibited additive antiviral activity. Together these results suggest that the host Hsc70 is a new antiviral target and that its inhibitors utilise a new mechanism of action.

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Section: Methodsmentioning

confidence: 99%

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Khachatoorian

Riahi

Ganapathy

et al. 2016

International Journal of Antimicrobial Agents

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“…Bearing a unique 4-ring core scaffold, compound 1 strongly provoked our interest to explore its anti-HCV structure-activity relationship (SAR) in an effort to discover a new chemical entity (NCE) against HCV with a novel mechanism. SAR studies have been carried out in our lab, revealing that the 5 S configuration in the core scaffold is beneficial for anti-HCV activity 15 , 16 . In the present study, the 5 S configuration was maintained and further SAR analysis was directed toward the carbon-carbon double bond in sophocarpine ( 2 , Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents

Peng

Gao

et al. 2014

Acta Pharmaceutica Sinica B

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Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonyl Δβγ sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation.

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“…DSG is associated with the EEVD domain in the C-terminal of Hsc70 and Hsp90 55 . N-substituted benzyl matrinic acid derivatives, ( + )-lycoricidine and analogs inhibited HCV replication through suppression of Hsc70 expression 53 , 54 , 56 .…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Lee

et al. 2017

Sci Rep

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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.

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N-Substituted Benzyl Matrinic Acid Derivatives Inhibit Hepatitis C Virus (HCV) Replication through Down-Regulating Host Heat-Stress Cognate 70 (Hsc70) Expression

Cited by 19 publications

References 21 publications

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly

Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents

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

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