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Soraphen A (SorA) is a naturally occuring myxobacterial metabolite that inhibits the acetyl-CoA carboxylase, a key enzyme in lipid biosynthesis. It was previously reported that SorA can efficiently inhibit the human immunodeficiency virus (HIV). 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.
| Targets |
Natural product; acetyl-CoA carboxylase; HIV; HCV
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|---|---|
| ln Vitro |
Soraphen A (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.[1]
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| Enzyme Assay |
Electron microscopy analyses [1]
This method was employed as previously described. Briefly, Huh7/Lunet cells were electroporated with 5µg of in vitro transcripts using full-length virus Jc1. Subsequently, 3x 104 12 cells were seeded in a 24-well plate with medium containing the indicated concentrations of DMSO, SorA or DCV. Cells were incubated for 96h with a medium change after 48h again adding the indicated inhibitor concentrations. Next, cells were fixed for indicrect immunofluorescence (IF) analysis (4% paraformaldehyde in PBS, 10'), electron microscopy (EM; 2.5% glutaraldehyde in 50 mM sodium cacodylate buffer[pH 7.2] containing 1M KCl, 0.1M MgCl2, 0.1M CaCl2 and 2% sucrose, 30’) or harvested for western blot (WB) analysis using 2x SDS sample buffer (400 mM Tris [pH 8.8], 10 mM EDTA, 0.2% bromophenolblue, 20% sucrose, 3% SDS, and 2% betamercaptoethanol). |
| Cell Assay |
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.[1]
Luciferase assays and cell cytotoxicity (viability) assays [1] For standard infection assays Huh7/Scr cells were seeded at a density of 1.2 x 104 cells/well in 96- well plates. One day later cells were pre-incubated for 1h at 37ºC with the pertinent compounds and then inoculated with the virus and the compounds for 4h at 37ºC. HCVpp were left for 6h. Finally, virus-containing media was replaced by a fresh media-compounds mix. Firefly and Renilla luciferase activities were assayed 72h post infection with the Dual-Glo® Luciferase Assay System while cytotoxicity (viability) assays were carried out with the CytoTox-Glo™ Cytotoxicity Assay, according to manufacturer’s instructions, using a plate luminometer FLUOstar OPTIMA. Mean relative light units (RLU) were plotted as percentage relative to control infections (solvent without compounds) for both infectivity and cell viability. Infections were carried out in duplicates and measured in duplicates (mean ± SEM; n=4). Half maximal effective concentration (EC50) and half maximal cytotoxic concentration 50 (CC50) were estimated by non-linear regression of log inhibitor vs. normalized response and used to calculate the Selectivity Index (SI) value. HCV inhibition in Stable Replicon Cell Lines [1] To assess the inhibitory effect of SorA in stable replicon cell lines, the LucUbiNeo Con1-ET cells or the LucUbiNeo JFH1 cells were seeded into a 12-well plate at a density of 4 × 104 cells/well. One day later, SorA was added at different concentrations. The NS5A inhibitor DCV was used a positive control. As mock control, DMSO was added according to the highest inhibitor concentration used in the assay. After 72 hours of treatment, cells were washed, lysed, and analyzed by luciferase activity assay as described above. |
| References | |
| Additional Infomation |
Soraphen A is a macrolide and an agent highly effective against plant-pathogenic fungi. It was extensively researched for agricultural use until it was discovered to be a teratogen. It has a role as a bacterial metabolite, an EC 6.4.1.2 (acetyl-CoA carboxylase) inhibitor and a teratogenic agent. It is a macrolide, an ether, a cyclic hemiketal and an olefinic compound.
Soraphen A has been reported in Sorangium cellulosum with data available. |
| Molecular Formula |
C29H44O8
|
|---|---|
| Molecular Weight |
520.65486
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| Exact Mass |
520.304
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| CAS # |
122547-72-2
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| PubChem CID |
5281897
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.802
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
|
| Heavy Atom Count |
37
|
| Complexity |
737
|
| Defined Atom Stereocenter Count |
10
|
| SMILES |
C[C@H]1C=C[C@H]([C@H](CCCC[C@@H](C2=CC=CC=C2)OC(=O)[C@@H](C)[C@@]3([C@@H]([C@H]([C@H](C)[C@H]1O3)O)OC)O)OC)OC
|
| InChi Key |
WPMGNXPRKGXGBO-OFQQMTDKSA-N
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| InChi Code |
InChI=1S/C29H44O8/c1-18-16-17-24(34-5)23(33-4)15-11-10-14-22(21-12-8-7-9-13-21)36-28(31)20(3)29(32)27(35-6)25(30)19(2)26(18)37-29/h7-9,12-13,16-20,22-27,30,32H,10-11,14-15H2,1-6H3/b17-16+/t18-,19-,20+,22-,23-,24+,25-,26-,27+,29+/m0/s1
|
| Chemical Name |
(1R,2S,5S,10S,11R,12E,14S,15S,16S,17S,18R)-1,17-dihydroxy-10,11,18-trimethoxy-2,14,16-trimethyl-5-phenyl-4,19-dioxabicyclo[13.3.1]nonadec-12-en-3-one
|
| Synonyms |
Soraphen A; 122547-72-2; CHEBI:9200; (1R,2S,5S,10S,11R,12E,14S,15S,16S,17S,18R)-1,17-dihydroxy-10,11,18-trimethoxy-2,14,16-trimethyl-5-phenyl-4,19-dioxabicyclo[13.3.1]nonadec-12-en-3-one; (1R,2S,5S,10S,11R,12Z,14S,15S,16S,17S,18R)-1,17-Dihydroxy-10,11,18-trimethoxy-2,14,16-trimethyl-5-phenyl-4,19-dioxabicyclo[13.3.1]nonadec-12-en-3-one; S1A; 3jrx; Soraphen A1.alpha.;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9207 mL | 9.6034 mL | 19.2068 mL | |
| 5 mM | 0.3841 mL | 1.9207 mL | 3.8414 mL | |
| 10 mM | 0.1921 mL | 0.9603 mL | 1.9207 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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