Soraphen A: A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity

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• 作者：George Koutsoudakis¹ ; ^# ; Iné ; s Romero-Brey² ; ^&dagger ; ; Carola Berger² ; ^&dagger ; ; Gemma Pé ; rez-Vilaró ; ¹ ; Paula Monteiro Perin³ ; ⁴ ; Florian Wolfgang Rudolf Vondran⁴ ; ⁵ ; Markus Kalesse⁶ ; Kirsten Harmrolfs⁷ ; Rolf Mü ; ller⁷ ; Javier P. Martinez⁸ ; Thomas Pietschmann³ ; ⁴ ; Ralf Bartenschlager² ; ⁹ ; Mark Br&ouml ; nstrup⁶ ; Andreas Meyerhans⁸ ; ¹⁰ ; Juana Dí ; ez¹ ; ^{juana.diez@upf.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HCV ; hepatitis C virus ; HIV ; human immunodeficiency virus ; VLDL ; very low density lipoprotein ; LDL ; low density lipoprotein ; ACC ; acetyl-CoA carboxylase ; SorA ; Soraphen A ; DMVs ; double membrane vesicles ; HCVcc ; cell culture-derived HCV ; TOFA ; 5-(tetradecyloxy)-2-furoic acid ; MOI ; multiplicity of infection ; EC50 ; half maximal effective concentration ; CC50 ; half maximal cytotoxic concentration ; SI ; selectivity index ; 2&prime ; -C-Met ; 2&prime ; -C-methyladenosine ; PHHs ; primary human hepatocytes ; TCID
• 刊名：Journal of Hepatology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：63
• 期：4
• 页码：813-821
• 全文大小：2118 K

文摘

Soraphen A (SorA) is a myxobacterial metabolite that inhibits the acetyl-CoA carboxylase, a key enzyme in lipid biosynthesis. We have previously identified SorA to efficiently inhibit the human immunodeficiency virus (HIV). The aim of the present study was to evaluate the capacity of SorA and analogues to inhibit hepatitis C virus (HCV) infection.

Methods

SorA inhibition capacity was evaluated in vitro using cell culture derived HCV, HCV pseudoparticles and subgenomic replicons. Infection studies were performed in the hepatoma cell line HuH7/Scr and in primary human hepatocytes. The effects of SorA on membranous web formation were analysed by electron microscopy.

Results

SorA potently inhibits HCV infection at nanomolar concentrations. Obtained EC₅₀ values were 0.70 nM with a HCV reporter genome, 2.30 nM with wild-type HCV and 2.52 nM with subgenomic HCV replicons. SorA neither inhibited HCV RNA translation nor HCV entry, as demonstrated with subgenomic HCV replicons and HCV pseudoparticles, suggesting an effect on HCV replication. Consistent with this, evidence was obtained that SorA interferes with formation of the membranous web, the site of HCV replication. Finally, a series of natural and synthetic SorA analogues helped to establish a first structure–activity relationship.

Conclusions

SorA has a very potent anti-HCV activity. Since it also interferes with the membranous web formation, SorA is an excellent tool to unravel the mechanism of HCV replication.