Details
| Original language | English |
|---|---|
| Pages (from-to) | 813-821 |
| Number of pages | 9 |
| Journal | Journal of hepatology |
| Volume | 63 |
| Issue number | 4 |
| Publication status | Published - 1 Oct 2015 |
| Externally published | Yes |
Abstract
Background & Aims 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.
Keywords
- Broad-spectrum antiviral, HCV replication inhibitor, HCV/HIV co-infection, Lipid metabolism, Natural product
ASJC Scopus subject areas
- Medicine(all)
- Hepatology
Sustainable Development Goals
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In: Journal of hepatology, Vol. 63, No. 4, 01.10.2015, p. 813-821.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Soraphen A
T2 - A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity
AU - Koutsoudakis, George
AU - Romero-Brey, Inés
AU - Berger, Carola
AU - Pérez-Vilaró, Gemma
AU - Monteiro Perin, Paula
AU - Vondran, Florian Wolfgang Rudolf
AU - Kalesse, Markus
AU - Harmrolfs, Kirsten
AU - Müller, Rolf
AU - Martinez, Javier P.
AU - Pietschmann, Thomas
AU - Bartenschlager, Ralf
AU - Brönstrup, Mark
AU - Meyerhans, Andreas
AU - Díez, Juana
N1 - Funding information: We thank Heinrich Steinmetz and Dr. Rolf Jansen for the natural soraphen analogues. The authors are supported by grants BFU2013-44629-R (to JD, GK and GPV), SAF2013-46077-R (to AM and JM), both from the Spanish Ministry of Economy and Competitiveness and FEDER , and from the German Centre for Infection Research (DZIF, to MB and RM).
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Background & Aims 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.
AB - Background & Aims 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.
KW - Broad-spectrum antiviral
KW - HCV replication inhibitor
KW - HCV/HIV co-infection
KW - Lipid metabolism
KW - Natural product
UR - http://www.scopus.com/inward/record.url?scp=84941944590&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2015.06.002
DO - 10.1016/j.jhep.2015.06.002
M3 - Article
C2 - 26070407
AN - SCOPUS:84941944590
VL - 63
SP - 813
EP - 821
JO - Journal of hepatology
JF - Journal of hepatology
SN - 0168-8278
IS - 4
ER -