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

Koutsoudakis, George; Romero-Brey, Inés; Berger, Carola; Pérez Vilaró, Gemma, 1985-; Monteiro Perin, Paula; Vondran, Florian Wolfgang Rudolf; Kalesse, Markus; Harmrolfs, Kirsten; Müller, Rolf; Martínez, Javier P.; Pietschmann, Thomas; Bartenschlager, Ralf; Brönstrup, Mark; Meyerhans, Andreas; Díez Antón, Juana, 1962-

doi:http://dx.doi.org/10.1016/j.jhep.2015.06.002

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

Citation

Koutsoudakis G, Romero-Brey I, Berger C, Pérez-Vilaró G, Monteiro Perin P, Vondran FW, Kalesse M, Harmrolfs K, Müller R, Martinez JP, Pietschmann T, Bartenschlager R, Brönstrup M, Meyerhans A, Díez J. Soraphen A: A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity. J Hepatol. 2015 Oct; 63(4): 813-21. DOI: 10.1016/j.jhep.2015.06.002

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./nRESULTS:/nSorA 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./nCONCLUSIONS:/nSorA 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.