PMID: 

Chem Pharm Bull (Tokyo). 2005 Feb ;53(2):244-7. PMID: 15684529

Abstract Title: 

Bioactive pyranoxanthones from the roots of Calophyllum blancoi.

Abstract: 

Phytochemical investigation of the roots of Calophyllum blancoi growing in Taiwan resulted in the isolation of three new pyranoxanthones, blancoxanthone (1), acetyl blancoxanthone (2) and 3-hydroxyblancoxanthone (3), in addition to two known pyranoxanthones, pyranojacaeubin (4) and caloxanthone (5). Structural characterization of the isolated compounds was determined by spectral analyses especially 2-D NMR. Biological study of the isolated xanthones revealed that blancoxanthone (1) exhibited significant anti-coronavirus activity.

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PMID: 

Chin Med J (Engl). 2005 Mar 20 ;118(6):493-6. PMID: 15788131

Abstract Title: 

Antiviral activity of cepharanthine against severe acute respiratory syndrome coronavirus in vitro.

Abstract: 

[n/a]

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PMID: 

Antiviral Res. 2005 Oct ;68(1):36-42. PMID: 16115693

Abstract Title: 

Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds.

Abstract: 

The 3C-like protease (3CLpro) of SARS-coronavirus mediates the proteolytic processing of replicase polypeptides 1a and 1ab into functional proteins, becoming an important target for the drug development. In this study, Isatis indigotica root extract, five major compounds of I. indigotica root, and seven plant-derived phenolic compounds were tested for anti-SARS-CoV 3CLpro effects using cell-free and cell-based cleavage assays. Cleavage assays with the 3CLpro demonstrated that IC50 values were in micromolar ranges for I. indigotica root extract, indigo, sinigrin, aloe emodin and hesperetin. Sinigrin (IC50: 217 microM) was more efficient in blocking the cleavage processing of the 3CLpro than indigo (IC50: 752 microM) and beta-sitosterol (IC50: 1210 microM) in the cell-based assay. Only two phenolic compounds aloe emodin and hesperetin dose-dependently inhibited cleavage activity of the 3CLpro, in which the IC50 was 366 microM for aloe emodin and 8.3 microM for hesperetin in the cell-based assay.

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PMID: 

Clin Exp Pharmacol Physiol. 2006 Jul ;33(7):612-6. PMID: 16789928

Abstract Title: 

Antiviral effects of saikosaponins on human coronavirus 229E in vitro.

Abstract: 

1. Saikosaponins represent a group of oleanane derivatives, usually as glucosides, that are found in a number of plant families. Saikosaponins isolated from medicinal plants such as Bupleurum spp., Heteromorpha spp. and Scrophularia scorodonia have been reported to possess various biological activities, specifically antihepatitis, antinephritis, antihepatoma, anti-inflammation, immunomodulation and antibacterial effects. 2. The aim of the present study was to examine the anticoronaviral activity of saikosaponins (A, B2, C and D) and their mode of action. Using the 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-5-[(phenylamino) carbonyl-2H-tetrazolium hydroxide] (XTT) assay, results showed that all saikosaponins tested demonstrated antiviral activity at concentrations of 0.25-25 micromol/L, with the strongest activity being noted for saikosaponin B2 (IC50 = 1.7 +/- 0.1 micromol/L). Interestingly, both saikosaponins A (50% cellular cytotoxicity (CC50) concentration = 228.1 +/- 3.8 micromol/L; selectivity index (SI) = 26.6) and B2 (CC50 = 383.3 +/- 0.2 micromol/L; SI = 221.9) exhibited no cytotoxic effects on target cells at concentrations that achieved antiviral activity. In the time-of-addition studies, saikosaponin B2, at 6 micromol/L, significantly inhibited human coronavirus 229E infection following its addition at various time pre-infection (-4 to -1 h), coinfection (0 h) and post-infection (1-4 h). Furthermore, saikosaponin B2 also showed an inhibitory effect on viral attachment and penetration. 3. The present results indicate that saikosaponin B2 has potent anticoronaviral activity and that its mode of action possibly involves interference in the early stage of viral replication, such as absorption and penetration of the virus.

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PMID: 

Bioorg Med Chem. 2006 Dec 15 ;14(24):8295-306. Epub 2006 Oct 12. PMID: 17046271

Abstract Title: 

Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features.

Abstract: 

The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-beta-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Gln189 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL(pro) were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.

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PMID: 

J Asian Nat Prod Res. 2007 Jan-Feb;9(1):59-65. PMID: 17365191

Abstract Title: 

Bioactive coumarins from Boenninghausenia sessilicarpa.

Abstract: 

Bioassay guided fractionation of Boenninghausenia sessilicarpa (Rutaceae) resulted in the isolation of a new dimeric coumarin glucoside 9'-methoxyl rutarensin (1) and a cytotoxic compound rutamarin (4), as well as an antivirus component leptodactylone (8), together with six known coumarins. Their structures were elucidated by 1D- and 2D NMR spectroscopy and ESI-MS analyses, respectively. Rutamarin (4) showed significant inhibitory activities against A-549, Bel-7402, HepG-2 and HCT-8 tumour cell lines with IC50s of 1.318, 2.082, 2.306 and 2.497 microg/ml. In addition, leptodactylone (8) showed potent protective activity on cells infected by SARS-CoV with ratio of 60% at 100 microg/ml.

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PMID: 

J Clin Virol. 2008 Feb ;41(2):122-8. Epub 2007 Nov 26. PMID: 18036887

Abstract Title: 

In vitro inhibition of coronavirus replications by the traditionally used medicinal herbal extracts, Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, and Phellodendron cortex.

Abstract: 

BACKGROUND: A search for new anti-coronaviral drugs to treat coronaviral infections was motivated by an outbreak of severe acute respiratory syndrome (SARS).OBJECTIVES: In order to find drugs that treat coronavirus infections, including SARS, we screened traditional medicinal herbal extracts and evaluated their antiviral activities on coronavirus replication.STUDY DESIGN: We employed a plaque assay to evaluate the effect of 22 medicinal herbal extracts on virus replication. We determined the 50% effective concentration (EC50) of each extract that was necessary to inhibit the replication of mouse hepatitis virus A59 (MHV-A59); we also determined 50% cytotoxic concentrations (CC50) for each extract. Northern and Western blot analyzes were performed to investigate antiviral activity in MHV-infected DBT cells, including virus entry, viral RNA and protein expression, and virus release. Coronavirus specific inhibition was also demonstrated using porcine epidemic diarrhea virus (PEDV).RESULTS: Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, Phellodendron cortex and Sophora subprostrata radix decreased the MHV production and the intracellular viral RNA and protein expression with EC50 values ranging from 2.0 to 27.5 microg/ml. These extracts also significantly decreased PEDV production and less dramatically decreased vesicular stomatitis virus (VSV) production in vitro.CONCLUSIONS: The extracts selected strongly inhibited MHV replication and could be potential candidates for new anti-coronavirus drugs.

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PMID: 

Antiviral Res. 2009 Jan ;81(1):77-81. Epub 2008 Nov 6. PMID: 18992773

Abstract Title: 

Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus.

Abstract: 

Porcine epidemic diarrhea virus (PEDV) is the predominant cause of severe entero-pathogenic diarrhea in swine. The lack of effective therapeutical treatment underlines the importance of research for new antivirals. In this study, we identified Q7R, which actively inhibited PEDV replication with a 50% inhibitory concentration (IC(50)) of 0.014 microg/mL. The 50% cytotoxicity concentration (CC(50)) of Q7R was over 100 microg/mL and the derived therapeutic index was 7142. Several structural analogues of Q7R, quercetin, apigenin, luteolin and catechin, also showed moderate anti-PEDV activity. Antiviral drugs and natural compounds revealed ribavirin, interferon-alpha, coumarin and tannic acid have relative weaker efficacy compared to Q7R. Q7R did not directly interact with or inactivate PEDV particles and affect the initial stage of PEDV infection by interfering of PEDV replication. Also, the effectiveness of Q7R against the other two viruses (TGEV, PRCV) was lower compared to PEDV. Q7R could be considered as a lead compound for development of anti-PEDV drugs to may be used to during the early stage of PEDV replication and the structure-activity data of Q7R may usefully guideline to design other related antiviral agents.

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PMID: 

Virus Res. 2010 Apr ;149(1):86-94. Epub 2010 Jan 21. PMID: 20096315

Abstract Title: 

Avian coronavirus infectious bronchitis virus susceptibility to botanical oleoresins and essential oils in vitro and in vivo.

Abstract: 

Anti-coronaviral activity of a mixture of oleoresins and essential oils from botanicals, designated QR448(a), was examined in vitro and in vivo. Treatment of avian infectious bronchitis virus (IBV) with QR448(a) reduced the virus titer as measured in two laboratory host systems, Vero E6 cells and embryonating eggs. The effect of QR448(a) on IBV in chickens was also investigated. Administering QR448(a) to chickens at a 1:20 dilution by spray, 2h before challenge with IBV was determined to be the most effective treatment. Treatment decreased the severity of clinical signs and lesions in the birds, and lowered the amount of viral RNA in the trachea. Treatment with QR448(a) protected chickens for up to 4 days post-treatment from clinical signs of disease (but not from infection) and decreased transmission of IBV over a 14-day period. Anti-IBV activity of QR448(a) was greater prior to virus attachment and entry indicating that the effect is virucidal. In addition, QR448(a) had activity against both Massachusetts and Arkansas type IB viruses, indicating that it can be expected to be effective against IBV regardless of serotype. To our knowledge, this is the first report on the in vivo use of a virucidal mixture of compounds effective against the coronavirus IBV.

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PMID: 

Int J Food Microbiol. 2010 Jul 31 ;141 Suppl 1:S91-7. Epub 2010 Jan 4. PMID: 20106541

Abstract Title: 

Lactic acid bacteria efficiently protect human and animal intestinal epithelial and immune cells from enteric virus infection.

Abstract: 

This study aimed to examine the potential antiviral activity of lactic acid bacteria (LAB) using animal and human intestinal and macrophage cell line models of non tumor origin. To this end, LAB strains selected on the basis of previous in vitro trials were co-incubated with cell line monolayers, which were subsequently challenged with rotavirus (RV) and transmissible gastroenteritis virus (TGEV). In order to elucidate the possible mechanism responsible for the antiviral activity, the induction of reactive oxygen species (ROS) release as well as the attachment ability of LAB on the cell lines was investigated. Various strains were found to exhibit moderate to complete monolayer protection against viral RV or TGEV disruption. Highest protection effects were recorded with the known probiotics Lactobacillus rhamnosus GG and Lactobacillus casei Shirota against both RV and TGEV, while notable antiviral activity was also attributed to Enterococcus faecium PCK38, Lactobacillus fermentum ACA-DC179, Lactobacillus pentosus PCA227 and Lactobacillus plantarum PCA236 and PCS22, depending on the cell line and virus combination used. A variable increase (of up to 50%) on the release of NO(-) and H(2)O(2) (ROS) was obtained when LAB strains were co-incubated with the cell lines, but the results were found to be LAB strain and cell line specific, apart from a small number of strains which were able to induce strong ROS release in more than one cell line. In contrast, the ability of the examined LAB strains to attach to the cell line monolayers was LAB strain but not cell line specific. Highest attachment ability was observed with L. plantarum ACA-DC 146, L. paracasei subsp. tolerans ACA-DC 4037 and E. faecium PCD71. Clear indications on the nature of the antiviral effect were evident only in the case of the L. casei Shirota against TGEV and with L. plantarum PCA236 against both RV and TGEV. In the rest of the cases, each interaction was LAB-cell line-virus specific, barring general conclusions. However, it is probable that more than one mechanism is involved in the antiviral effect described here. Further investigations are required to elucidate the underlying mode of action and to develop a cell line model as a system for selection of probiotic strains suited for farm animal applications.

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