lignans and Hepatitis-B

Despite that some approved drugs and genetically engineered vaccines against hepatitis B virus (HBV) are available for HBV patients, HBV infection is still a severe public health problem in the world. All the approved therapeutic drugs (including interferon-alpha and nucleoside analogues) have their limitations. No drugs or therapeutic methods can cure hepatitis B so far. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially non-nucleoside agents. Naturally originated compounds with enormous molecular complexity and diversity offer a great opportunity to find novel anti-HBV lead compounds with specific antiviral mechanisms. In this review, the natural products against HBV are discussed according to their chemical classes such as terpenes, lignans, phenolic acids, polyphenols, lactones, alkaloids and flavonoids. Furthermore, novel mode of action or new targets of some representative anti-HBV natural products are also discussed. The aim of this review is to report new discoveries and updates pertaining to anti-HBV natural products in the last 20 years, especially novel skeletons and mode of action. Although many natural products with various skeletons have been reported to exhibit potent anti-HBV effects to date, scarcely any of them are found in the list of conventional anti-HBV drugs worldwide. Additionly, in anti-HBV mechanism of action, only a few references reported new targets or novel mode of action of anti-HBV natural products.

Topics: Alkaloids; Antiviral Agents; Biological Products; Flavonoids; Hepatitis B; Hepatitis B virus; Humans; Hydroxybenzoates; Lactones; Lignans; Molecular Structure; Polyphenols; Terpenes

Hepatitis B virus (HBV) infection is a severe health problem all over the world. However, there is still no satisfactory anti-HBV therapeutic strategy. Currently, promising alternative approaches toward the control of HBV infection include the development of structurally novel and more potent inhibitors obtained from natural products and structural modifications of synthetic molecules as seen in many cases. In this review, we will focus our interest on representative naturally occurring and synthetic small molecule non-nucleoside inhibitors with high anti-HBV potency and potential for future therapeutic regimens to combat HBV infection.

Topics: Alkaloids; Antiviral Agents; Biological Products; Flavanones; Hepatitis B; Heterocyclic Compounds; Humans; Lignans; Terpenes

Lignans are widely distributed in nature. The earliest recorded medicinal use of lignans dated back to over 1000 years ago. Lignan-rich plant products were also active ingredients in Chinese and Japanese folk medicines for the treatment of various diseases. The dried root and stem of this plant are listed in the Chinese pharmacopoeia for the treatment of rheumatoid arthritis, gastric, duodenal ulcers and many other diseases. This review highlights synthetic strategies for the Wuweizisu C analogs and the important pharmacological activities as well as therapeutic findings related to the treatment of HBV and other diseases. Notably a significant and ongoing project on Wuweizisu C and its analogs has led to the discovery and development of two potent derivatives alpha-DDB and BICYCLOL which are currently in clinical trials against HBV, especially in lowering elevated SGPT levels. Further design, synthesis, and evaluation of Wuweizisu C analogs are discussed.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Biological Products; Cyclooctanes; Hepatitis B; Humans; Lignans; Neoplasms; Polycyclic Compounds

The plants of the genus Phyllanthus (Euphorbiaceae) are widely distributed in most tropical and subtropical countries, and have long been used in folk medicine to treat kidney and urinary bladder disturbances, intestinal infections, diabetes, and hepatitis B. In recent years, the interest in the plants has increased considerably. Substantial progress on their chemistal and pharmacological properties, as well as a few clinical studies of some Phyllanthus species have been made. This review discusses the current knowledge of their chemistry, the in vitro and in vivo pharmacological, biochemical, and clinical studies carried out on the extracts, and the main active constituents isolated from different species of plants of the genus Phyllanthus. These studies carried out with the extracts and purified compounds from these plants support most of their reported uses in folk medicine as an antiviral, in the treatment of genitourinary disorders, and as antinociceptive agents. However, well-controlled, double-binding clinical trials are lacking. Several compounds including alkaloids, flavonoids, lignans, phenols, and terpenes were isolated from these plants and some of them interact with most key enzymes. Together this data strongly supports the view that the plants belonging to the genus Phyllanthus have potential beneficial therapeutic actions in the management of hepatitis B, nefrolitiase, and in painful disorders.

Topics: Alkaloids; Analgesics; Animals; Antiviral Agents; Brazil; Diabetes Mellitus; Euphorbiaceae; Flavonoids; Hepatitis B; Humans; Intestinal Diseases; Kidney Diseases; Lignans; Medicine, Traditional; Phenols; Phytotherapy; Plant Extracts; Plants, Medicinal; Terpenes; Tropical Climate; Urinary Bladder Diseases

Niranthin is a lignan isolated from Phyllanthus niruri L. This plant has long been used in folk medicine for liver protection and antihepatitis B in many Asian countries. This study was designed to evaluate the anti-hepatitis B virus activity of niranthin using HepG2.2.15 cells and duck hepatitis B virus (DHBV) infected ducks as in vitro and in vivo models.. Niranthin was isolated from Phyllanthus niruri L. (Euphorbiaceae) by extraction and chromatographic procedures and the anti-hepatitis B virus activity was evaluated both in vitro and in vivo. The human HBV-transfected liver cell line HepG2.2.15 was used in vitro assay. And the in vivo anti-hepatitis B virus activity was evaluated on the expression of HBV replication, HBsAg, HBeAg, ALT and AST on day 0, 7, 14, 17 after niranthin was dosed intragastricly (i.g.) once a day for 14 days at the dosages of 25, 50 and 100 mg/kg/day in the duck hepatitis B virus (DHBV) infected ducks.. In the human HBV-transfected liver cell line HepG2.2.15, the secretion of HBsAg and HBeAg were significantly decreased after treatment with niranthin for 144 h, with IC50 values for HBsAg of 15.6 µM, IC50 values for HBeAg of 25.1 µM. In DHBV-infected ducklings, niranthin significantly reduced the serum DHBV DNA, HBsAg, HBeAg, ALT and AST. Furthermore, analysis of the liver pathological changes confirmed the hepatoprotective effect of niranthin.. The experimental data demonstrated that niranthin exhibits anti-hepatitis B virus activity both in vitro and in vivo.

Topics: Animals; Anisoles; Antiviral Agents; Dioxoles; Disease Models, Animal; Ducks; Female; Hep G2 Cells; Hepadnaviridae Infections; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B Virus, Duck; Hepatitis, Viral, Animal; Humans; Inhibitory Concentration 50; Lignans; Male; Phyllanthus

Nirtetralin B, a new lignan first reported by our team, is isolated from Phyllanthus niruri L. This plant has long been used in folk medicine for liver protection and antihepatitis B in many Asian countries. This study was designed to evaluate the anti-hepatitis B virus activity of nirtetralin B using HepG2.2.15 cells and duck hepatitis B virus (DHBV) infected ducks as in vitro and in vivo models.. Nirtetralin B was isolated from Phyllanthus niruri L. (Euphorbiaceae) by extraction and chromatographic procedures and the anti-hepatitis B virus activity was evaluated both in vitro and in vivo. The human HBV-transfected liver cell line HepG2.2.15 was used in vitro assay. And the in vivo anti-hepatitis B virus activity was evaluated on the expression of HBV replication, HBsAg, HBeAg, ALT and AST on day 0, 7, 14, 17 after nirtetralin B was dosed intragastricly (i.g.) once a day for 14 days at the dosages of 25, 50 and 100mg/kg/day in the duck hepatitis B virus (DHBV) infected ducks.. In the human HBV-transfected liver cell line HepG2.2.15, nirtetralin B effectively suppressed the secretion of the HBV antigens in a dose-dependent manner with IC50 values for HBsAg of 17.4μM, IC50 values for HBeAg of 63.9μM. In DHBV-infected ducklings, nirtetralin B significantly reduced the serum DHBV DNA, HBsAg, HBeAg, ALT and AST. And analysis of the liver pathological changes confirmed the hepatoprotective effect of nirtetralin B.. The experimental data demonstrated that nirtetralin B exhibits anti-hepatitis B virus activity both in vitro and in vivo.

Topics: Animals; Anisoles; Antiviral Agents; Dioxoles; Dose-Response Relationship, Drug; Ducks; Female; Hep G2 Cells; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B Virus, Duck; Humans; Inhibitory Concentration 50; Lignans; Male; Medicine, Traditional; Phyllanthus; Virus Replication

Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure-activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC50=0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.

Topics: Antiviral Agents; DNA, Viral; Gene Expression Regulation, Viral; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Lignans; RNA, Viral; Structure-Activity Relationship

The extracts from leaves, heartwood, barks and roots of the Streblus asper were investigated for anti-HBV activities, separately. The results suggested that the MeOH extracts of the heartwood, barks, and roots exhibited good anti-HBV activities. Further investigations displayed that ethyl acetate and n-butanol soluble parts of their MeOH extracts showed more significant anti-HBV activities. Moreover, a new lignan, together with 11 known compounds, was isolated from n-butanol-soluble part of MeOH extract of the roots of S. asper. The structures were elucidated by spectroscopic methods, including 1D NMR ((1)H NMR, (13)C NMR), 2D NMR (HMQC, HMBC) and HR-EI-MS experiments. Compounds 1-3 were evaluated for their anti-HBV activities. Honokiol showed significant anti-HBV activity with IC(50) values of 3.14μM and 4.74μM for HBsAg and HBeAg with no cytotoxicity respectively, while lamivudine (3TC, positive control) exhibited weak anti-HBV activity with IC(50) values of 11.81μM and 25.80μM for HBsAg and HBeAg respectively.

Topics: Antiviral Agents; Biphenyl Compounds; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Inhibitory Concentration 50; Lamivudine; Lignans; Molecular Structure; Moraceae; Phytotherapy; Plant Extracts; Plant Roots; Plant Structures

Two new lignans, dihydrodehydrodiconiferyl alcohol 9-O-β-D-(3″-O-acetyl)-xylopyranoside (1) and threo-4,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan 7-O-α-rhamnopyranoside (2) were isolated from Illicium henryi, together with ten known compounds, 3-12. Their structures were elucidated by extensive spectroscopic analyses. The anti-hepatitis B virus (anti-HBV) activity of compounds 1-12 inhibiting HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion on Hep G2.2.15 cell line was evaluated. (-)-Dihydrodehydrodiconiferyl alcohol (4) showed moderate inhibitory activity on both HBsAg and HBeAg secretion with IC(50) values of 0.06 and 0.53 mM, respectively.

Topics: Antiviral Agents; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Illicium; Lignans; Molecular Structure; Plant Extracts

We have previously shown that helioxanthin can suppress human hepatitis B virus gene expression. A series of helioxanthin analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Modifications at the lactone rings and methylenedioxy unit of helioxanthin can modulate the antiviral activity. Among them, compound 32 is the most effective anti-HBV agent. Compound 32 can suppress the secretion of viral surface antigen and e antigen in HepA2 cells with EC(50) values of 0.06 and 0.14 microM, respectively. Compound 32 not only inhibited HBV DNA with wild-type and lamivudine-resistant strain but also suppressed HBV mRNA, core protein and viral promoters. In this study, a full account of the preparation, structure-activity relationships of helioxanthin analogues, and the possible mechanism of anti-HBV activity of this class of compounds are presented. This type of compounds possesses unique mode of action differing from existing therapeutic drugs. They are potentially new anti-HBV agents.

Topics: Cell Line, Tumor; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lignans; Promoter Regions, Genetic; Structure-Activity Relationship; Viral Core Proteins; Virus Replication

Chromium (Cr) concentration in the environment is increasing day by day due to its excessive use in leather processing, refractory steel, and chemical manufacturing industries. Excess Cr in the environment causes hazardous effects on all living beings including plants. In this context attempts have been made to see the effect of Cr on a very important medicinal plant Phyllanthus amarus Schum and Thonn. It has focused as a hepatoprotective plant curing hepatitis 'B' in modern research. The P. amarus seedlings of approximately same height and weight were grown in similar conditions in experimental garden. After 30 days plants were harvested and chlorophyll, protein, sugar, starch and secondary metabolites concentration were estimated in these plants as per standard methods. Besides ultramorphological variations in leaves and Cr accumulation in roots and aerial parts were also checked with the help of scanning electron microscope and atomic absorption spectrophotometer respectively. The study revealed that Cr causes significant decrease in fresh and dry weight, length of root and shoot, protein, sugar, chlorophyll and carotenoids in P. amarus. On the other hand it is interesting to note that the concentration of therapeutically active secondary metabolites - phyllanthin and hypophyllanthin increased up to certain level of Cr. It may be due to stress caused by the accumulation of Cr. Besides, ultramorphological changes viz. wide stomatal opening and less wax deposition on both the surfaces of leaves were also observed.

Topics: Chromium; Environmental Pollutants; Hepatitis B; Lignans; Microscopy, Electron, Scanning; Phyllanthus; Plant Extracts

Bioassay-directed fractionation of the EtOAc extract of Kadsura japonica has led to the isolation of six new C18 dibenzocyclooctadiene lignans, schizanrins I, J, K, L, M, N, along with four known C19 homolignans, taiwanschirins A, B, C, and heteroclitin F. The elucidations of the new structures were based on spectral analysis. Bioassay evaluation against human type B hepatitis revealed that taiwanschirins A and B showed strong activity for anti-HBsAg and a medium effect for anti-HBeAg at 25 microg/mL (12.9 and 11.9 microM for taiwanschirins A and B, respectively).

Topics: Antiviral Agents; Cell Line; Cyclooctanes; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Humans; Kadsura; Lignans; Magnetic Resonance Spectroscopy; Phytotherapy; Plant Extracts; Structure-Activity Relationship

This paper deals with a HPLC method for determining the content of gamma-schizandrin in Manganbao granules. Samples are extracted with haxane, re-dissolved in MeOH, chromatographed on HPLC (Column, Spheri-5 RP-18, 220 mm x 4. 6mm, mobile phase, 75% MeOH) and the main components can be easily isolated. Six samples were analyzed by calibration curve method. The results have shown that the quantitative analysis of gamma-schizandrin conducted in this way is convenient, fast and highly reproducible.

Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Cyclooctanes; Drug Combinations; Drugs, Chinese Herbal; Hepatitis B; Lignans; Polycyclic Compounds

Fructus Schizandrae (FS) is a well-known Chinese herb which has been widely used in ancient China. During recent decades, it has been found to be effective in viral and chemical induced hepatitis. In this paper, we report the studies on the chemical constituents and pharmacological actions of FS on mice liver. The results indicated that FS and its several components can mainly protect liver from injury induced by toxic substances such as CCl4; they have anti-oxidant activities against oxygen free radicals; FS and four components have inducing action on liver cytochrome P-450; they also promote certain anabolic metabolism such as serum protein biosynthesis and glycogenesis. All these activities would be of importance in the protection and repair of the injured liver cells. The clinical use of FS is also presented.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 Enzyme System; Dioxoles; Drugs, Chinese Herbal; Hepatitis B; Humans; Lignans; Lipid Peroxidation; Mice; Microsomes, Liver; Polycyclic Compounds; Rats