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More than 180 million people are infected with Hepatitis C virus (HCV) and are at risk of developing liver cirrhosis and/or hepatocellular carcinoma1, and the number of patients is also increase 3-4million per year. Since the discovery of HCV in 1989, dramatic progress has been made in the development of novel antiviral drugs. Up till now, more or less 70 anti-HCV agents are in process of clinical trials. Some of them are natural products or natural product-derived candidates. Natural products could play an important role as sources for searching anti-HCV agents. In this review, XX small-molecule natural products with their chemical structure, natural origin, bioactivity and pharmacology are discussed and listed.
Hepatitis C virus (HCV) infection may causes a series of liver diseases, such as chronical hepatitis, liver Cirrhosis and hepatocellular carcinoma which is the primary reason for liver transplantations among adults in western countries . Although HCV was first identified in 1989, it spread all over the world because of without effective vaccine. It is estimated that a minimum of 3% of the world's population (approximately 200 million people) are chronically infected, with additional approximately 3-4 million new cases of HCV infection each year. The standard of care for chronic hepatitis C is a combination of interferon-Î±(IFN-Î±) with ribavirin(RBV). IFN-Î± is the cytokine that not only acts through its antiviral effect, but also acts on the immune system of the host and ribavirin is a kind of the nucleoside analogue which has a wide antiviral spectrum. Despite this, the therapy achieves a sustained viral response (SVR) in only ~40% of genotype 1 patients in the US, Europe and Japan, and represents a large amount of health-care fund, which is likely to increase over the coming years. What's more, the long duration of treatment (24weeks for genotype 1) is difficult for patients to tolerate owing to side effects associated with IFN and RBV that include flu-like symptoms, fatigue, cognitive dysfunction, depression, cutanous reactions, gastrointestinal symptoms, pulmonary effects, cytopenias, thyroid dysfunction, retinopathy, and others [5,7].
HCV, belonging to the Flaviviridae family, exhibits a high degree of genetic variability. To date, six genotypes and more than 50 subtypes have been identified, with genotypes 1 and 2 being the most prevalent forms. That's just the difficulty for development effective vaccine. The HCV genome is a positive single strand RNA(ssRNA), which comprises a 5 non-translated region (NTR, ~340 nucleotides), a single open reading frame (ORF) of ~9,000 nucleotides in length and a short 3â€²NTR(~300 nucleotides). The ORF encodes a polyprotein of ~3,010 amino acids, which is cleaved at several sites by host signal peptidases and HCV encoded proteases to produce four structural proteins (C, E1,E2 and p7), and six non-structural (NS) proteins (NS2, NS3, NS4A NS4B,NS5A and NS5B).
2 Target for HCV inhibitor compounds
The non-structural protein NS3 possesses a protease domain that is responsible for the cis-cleavage of the NS3-NS4A junction and the trans-cleavage of the NS4B, NS5A, and NS5B junctions to deliver proteins essential for replication. After the HCV RNA encoded the polyprotein, the structural proteins are processed by host peptidases, whereas the nonstructural proteins are processed by two virally encoded proteases, the NS2/3 and the NS3 proteases. The NS2/3 protease is responsible for a single cleavage between NS2 and NS3, while the NS3 protease is responsible for the release of the remaining downstream nonstructural protein. NS4A acting as cofactor is important for the proteolytic activity of NS3. Efficient processing requires the NS3 protease in combination with the NS4A cofactor and a structural zinc molecule. According to many studies on expression, purification, and in vitro enzymatic reconstitution, the NS3 protease is perhaps the most thoroughly characterized HCV enzyme and the most intensively pursued HCV target.
NS5A, with its function is still not very clear, is phosphorylated protein in a 56 kDa basally phosphorylated form and in a 58 kDa hyperphosphorylated form. The phosphorylation state of NS5A was recently proposed to have a regulatory function in HCV RNA replication and was believed to be an essential component of the HCV replication complex. What's more, A region in NS5A, known as the interferon (IFN)-sensitivity-determining region (ISDR), has been linked to the response to IFN-Î± therapy in some strains of HCV. So some reviews published resently believed that NS5A is also a target for design anti-HCV compounds.(see review)Â
The protein NS5B is cleaved from the HCV polyprotein by the NS3 serine protease, and functions as a RNA-dependent RNA polymerase. It is the key enzyme for synthesis of a complementary minus-strand RNA, using the genome as a template, and the subsequent synthesis of genomic plus-strand RNA from this minus-strand RNA template. Similar to other polymerases, the structure of DENV RdRp exhibits a canonical right-hand conformation and consists of fingers, palm, and thumb domains. NS5B is crucial for viral infectivity and is a validated target for the development of therapeutics against HCV.
3.Natural Products for inhibition of HCV
Chinese herbal medicine has a long history for treatment various ailments. Natural products extracted from chinese medicine provide a huge compounds pool for assay various biological activities. In the past ten years, tens of natural products have been reported have anti-HCV properties. These natural products can be the leading compounds for discovery of anti-HCV drug candidates. Herein we review the progress in research on the natural products possessing anti-HCV activity, and list the compounds with their anti-HCV activity in table 1.
(-)-Mullein(1) (also known as ochracin) is a widely distributed dihydroisocoumarine derivative in fungi. It was isolated by Karsten K et al. from culture broths of the endopytic fungi Pezicula livida, Plectophomella sp., Cryptosporiopsis malicorticis and Cryptosporiopsis sp. in 1997. Jin-Rui D et al. also isolate (-)-Mullein from a crude extract of fungi Aspergillus ochraceus and find it inhibited HCV protease NS3 with an IC50 value of 35 Î¼M.
Very recently, MinKyun Na et al found that three known pyrroloiminoquinone alkaloids discorhabdins A(2), C(3), dihydrodiscorhabdin C(4) have significant antiviral activity against HCV with EC90 values all blow 10Î¼M. These compounds were isolated from a new deep-water Alaskan sponge species of the genus Latrunculia. The genus Latrunculia (class Demospongiae, order Poecilosclerida, family Latrunculiidae) is predominantly found in cold water regions such as Antarctica and the North Pacific, particularly in South Africa and New Zealand.
Eight Pseudoguaianolides(5-12) with potent inhibition of hepatitis C virus (HCV) replication were obtained from Parthenium hispitum and three of them were found to possess in vitro anti-HCV activity in the subgenomic HCV replicon system with significant inhibition above 90% at 2 Î¼M concentration. Furthermore, compounds 5 and 7 were also shown to inhibit HCV RNA level using the same cells and a branched DNA detection method for HCV NS3 RNA.
Parthenolide(13) ,a sesquiterpene lactone, is the putative active ingredient of feverfew (Tanacetum parthenium), one of the most commonly used medicinal herbs for fever and migraine in the United States. The compound also exhibits anti-HCV protease activity with an EC50 value of 2.21Î¼M against HCV replication in a subgenomic RNA replicon assay system. Furthermore, the experiment results showed that the efficacy of combination of 5 IU/mL IFN-Î± and 1.25 Î¼M parthenolide (1) in inhibiting HCV replication was similar to that of 10 IU/mL IFN-a alone. Parthenolide (1) therefore could possibly enhance the IFN-a-exerted anti-HCV activity in a dose-dependent manner. Several commercially available sesquiterpene lactones, including costunolide (14), dehydrocostus lactone (15), helenalin (16), alantolactone (17), structurally analogous to parthenolide also exhibit micromolar concentrations for anti-HCV activities(see table 1).
Iridoids, including aucubin (18), have been reported to possess antihepatitis or liver cirrhosis mitigating effects.[21,22]lamiridosins A and B (19,20) are iridoid isomers that were isolated from the aqueous extract of the flowering tops of Lamium album. These compounds were found to significantly inhibit hepatitis C virus entry (IC50 2.31 Î¼M) in vitro. In this study, evaluation of a commercially prepared aqueous extract of this plant material showed that it was active against HCV in an HCVpp (HCV pseudoparticles) entry assay. Lamiridosin A is the corresponding aglycone (nonsugar portion) of lamalbid (lamiridoside) which is isolated from a methanol extract of the same plant material and inactive against HCVpp. Lamiridosin B is inseparable epimer of A. To further evaluate of iridoids and its glucosides for anti-HCV host-cell entry activity, several commercially available iridoids, and their glucosides were tested their anti-HCV potentials. The iridoids glucosides are almost inactivity in contrast to iridoids aglycones which did exhibit significant inhibition against HCV entry(See table 1).
four (âˆ’)-Epicatechin derivatives were isolated on a crude ethanol extract from rhizomes of the Chinese medicinal herb Rhodiola kirilowii (Regel) Maxim using column chromatography (CC) techniques and tested for in vitro activity against HCV NS3 serine protease (NS3-SP) with the result that these compound IC50 values as 0.77, 0.91, 8.51 and18.55. T he activity of HCV NS3-SP in the expressed domain was assayed by enzyme-linked immunosorbent assay (ELISA) according to the reported method . R. kirilowii is a special medicinal plant indigenous to the high altitude of Qinghai-Tibet Plateau in China. Epicatechins as a polyphenols could be chemically classified as constituents of condensed tannin. The potent anti-NS3-SP activities would be reinforced by the increasing of free hydroxyl groups in the structure and weakened by the removal or blockade of the free hydroxyl groups. Once the hydroxyl groups were methylated or acylated, their activities decreased markedly. So the free hydroxyl groups in these compounds played an important role in the inhibitory effect on NS3-SP.
Glycyrrhizin is a natural compound extracted from the roots fo Glycyrrhiza glabra and is composed of one molecule of glycyrrhetinic acid and two molecule of glucuronic acid. It has been used for many centuries as an anti-allergic agent and food additive. In Japanese, Glycyrrhizin, as a constituent of Neo Minophagen C(SNMC), has been used as a treatment for chronic hepatitis for almost 30 years. SNMC is a solution for intravenous use consisting of 2mg glycyrrhizin, 1mg cystine and 20mg glycine per ml in physiological saline solution. A retrospective study suggest that long-term usage of SNMC is effective in preventing hepatocellular carcinoma development in patients with chronic hepatitis C. Recently study by Hidaka et al. demonstrate that SNMC protects hepatocytes against oxidative stress and mitochondrial injury in the presence of HCV proteins by restoring depleted cellular glutathione.
SCH68631, SCH351633, SCH644342 and SCH644343
During the search for new HCV protease inhibitors, several fungal metabolites were isolated by the same institutes(Schering-Plough Research Institute).SCH68631( )was a phenanthrenequinone derivates, discovered from microorganisms identified as a Streptomyces sp. (culture 94-02747), The microorganism was isolated from a loam soil in a wooded area of Nepal with RP soil isolation media in 1996. In vitro HCV protease scintillation proximity assay show the compounds inhibition with an IC50 value of 2.5 Î¼g/ml. Three years later, in 1999, another fungal metabolite(SCH351633,)was reported and exhibited inhibitory activity in the HCV protease assay with an IC50 value of 3.8Î¼g /ml. SCH351633 was was isolated from the fungus Penicillium griseofulvum (culture Mer-0442, designated as Schering Culture Collection Fungi, SCF-1704) by the same group. The microorganism was isolated from a soil sample collected from a desert terrain in the state of Arizona, U.S.
To investigate new natural products as leads for inhibiting HCV infection, several semi-purified fractions of aqueous methanolic extracts of many plants were screened at the same institute mentioned above. One of these fractions, which was derived from a plant identified as Stylogne cauliflora sp, was active in NS3/4A protease assay. Bioassay-guided fractionation of this extract led to the isolation of two oligo-phenols SCH644342 and SCH644343. Both compounds were active in the HCV NS3 protease activity assay, with IC50 values of 0.3 and 0.8Î¼M, respectively.
Silibinin (Silybin, Silybine)
Silymarin is a mixture of flavonolignans extracted from the milk thistle (Silybum marianum) that has been used for many years as a "hepatoprotector" agent. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. Recently, a number of advances hve been published on the character of silymarin's antiviral actions.Some research revealed that silymarin blocked HCVcc(infectious HCV particles) infection of human hepatoma cultures, inhibited TNF-Î± and TCR induced NFÎºB-dependent transcription, and suppressed TCR-mediated proliferation and inflammatory cytokine production from T cells[34,35]. Some others show that silymarin can also block in vitro HCV NS5B polymerase activity at high concentration. And a recent paper published on Hepatology displayed that silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus and blocked cell-to-cell spread of virus. So the author of this paper suggested that the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell. Although its mechanisms of action remain to be fully defined, silibinin, either as intravenous infusion or as oral administration(phospholipid-complexed), has been demonstrated that it might be useful against hepatitis C in chronically infected patients in clinical trails.
In a decade of extensive research, great progress has been achieved in the discovery of natural potent anti-HCV agents. Tens of natural products have been found with significant bioactivity of against Hepatitis C or directly inhibit HCV replication or entry. Among them, some molecules used as leading compounds in anti-HCV new drugs discovery. Although no plant-derived drug is currently in clinical use to treat HCV until now, some promising candidates from natural products or their derivatives and analogs have started clinical trials. We believe more and more natural products with their bioactivity will be discovered on the search for anti-HCV agents, which could play an more important role as sources for anti-HCV drugs design and discovery.