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Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry.

Lin LT, Chen TY, Lin SC, Chung CY, Lin TC, Wang GH, Anderson R, Lin CC, Richardson CD - BMC Microbiol. (2013)

Bottom Line: These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs).CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity.Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

ABSTRACT

Background: We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry.

Results: Extensive analysis of the tannins' mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.

Conclusions: CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.

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Related in: MedlinePlus

Inactivation of viral infections by CHLA and PUG. Different viruses were treated with the test compounds for a long period (incubated for 1.5 – 3 h before titration; light gray bars) or short period (immediately diluted; dark gray bars) at 37°C before diluting it 50 – 100 fold to sub-therapeutic concentrations and subsequent analysis of infection on the respective host cells. (A) Schematics of the experiment (shown on the left) with the final virus concentration (PFU/well or MOI), long-term virus-drug incubation period (i), and the subsequent incubation time (ii) indicated for each virus in the table on the right. Analyses for (B) HCMV, (C) HCV, (D) DENV-2, (E) MV, and (F) RSV are indicated in each additional panel. Results are plotted against the DMSO negative control treatment for virus infection and the data shown are the means ± SEM from three independent experiments. See text for details.
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Figure 3: Inactivation of viral infections by CHLA and PUG. Different viruses were treated with the test compounds for a long period (incubated for 1.5 – 3 h before titration; light gray bars) or short period (immediately diluted; dark gray bars) at 37°C before diluting it 50 – 100 fold to sub-therapeutic concentrations and subsequent analysis of infection on the respective host cells. (A) Schematics of the experiment (shown on the left) with the final virus concentration (PFU/well or MOI), long-term virus-drug incubation period (i), and the subsequent incubation time (ii) indicated for each virus in the table on the right. Analyses for (B) HCMV, (C) HCV, (D) DENV-2, (E) MV, and (F) RSV are indicated in each additional panel. Results are plotted against the DMSO negative control treatment for virus infection and the data shown are the means ± SEM from three independent experiments. See text for details.

Mentions: Viral inactivation assays were performed as previously described [33] and the incubation periods and viral dose used are listed in Figure 3A. Different viruses were mixed with the test compounds and incubated at 37°C (Figure 3A, long-term). The drug-virus mixtures were subsequently diluted (50 – 100 fold) to “sub-therapeutic” (ineffective) concentrations with low serum medium and then inoculated on to the respective host cells seeded in multiwell plates. The dilution to sub-therapeutic concentration prevents effective interaction between the drugs and the host cell surface. For comparison, viruses were also mixed with test compounds and immediately diluted (no incubation period) to sub-therapeutic concentration prior to infection (Figure 3A, short-term). Following incubation for viral absorption, the diluted inocula were removed and the wells were washed with PBS twice before applying the overlay medium. The plates were further incubated before being subjected to assessment by plaque assays, EGFP expression analysis, or luciferase assay as described above.


Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry.

Lin LT, Chen TY, Lin SC, Chung CY, Lin TC, Wang GH, Anderson R, Lin CC, Richardson CD - BMC Microbiol. (2013)

Inactivation of viral infections by CHLA and PUG. Different viruses were treated with the test compounds for a long period (incubated for 1.5 – 3 h before titration; light gray bars) or short period (immediately diluted; dark gray bars) at 37°C before diluting it 50 – 100 fold to sub-therapeutic concentrations and subsequent analysis of infection on the respective host cells. (A) Schematics of the experiment (shown on the left) with the final virus concentration (PFU/well or MOI), long-term virus-drug incubation period (i), and the subsequent incubation time (ii) indicated for each virus in the table on the right. Analyses for (B) HCMV, (C) HCV, (D) DENV-2, (E) MV, and (F) RSV are indicated in each additional panel. Results are plotted against the DMSO negative control treatment for virus infection and the data shown are the means ± SEM from three independent experiments. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750913&req=5

Figure 3: Inactivation of viral infections by CHLA and PUG. Different viruses were treated with the test compounds for a long period (incubated for 1.5 – 3 h before titration; light gray bars) or short period (immediately diluted; dark gray bars) at 37°C before diluting it 50 – 100 fold to sub-therapeutic concentrations and subsequent analysis of infection on the respective host cells. (A) Schematics of the experiment (shown on the left) with the final virus concentration (PFU/well or MOI), long-term virus-drug incubation period (i), and the subsequent incubation time (ii) indicated for each virus in the table on the right. Analyses for (B) HCMV, (C) HCV, (D) DENV-2, (E) MV, and (F) RSV are indicated in each additional panel. Results are plotted against the DMSO negative control treatment for virus infection and the data shown are the means ± SEM from three independent experiments. See text for details.
Mentions: Viral inactivation assays were performed as previously described [33] and the incubation periods and viral dose used are listed in Figure 3A. Different viruses were mixed with the test compounds and incubated at 37°C (Figure 3A, long-term). The drug-virus mixtures were subsequently diluted (50 – 100 fold) to “sub-therapeutic” (ineffective) concentrations with low serum medium and then inoculated on to the respective host cells seeded in multiwell plates. The dilution to sub-therapeutic concentration prevents effective interaction between the drugs and the host cell surface. For comparison, viruses were also mixed with test compounds and immediately diluted (no incubation period) to sub-therapeutic concentration prior to infection (Figure 3A, short-term). Following incubation for viral absorption, the diluted inocula were removed and the wells were washed with PBS twice before applying the overlay medium. The plates were further incubated before being subjected to assessment by plaque assays, EGFP expression analysis, or luciferase assay as described above.

Bottom Line: These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs).CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity.Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

ABSTRACT

Background: We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry.

Results: Extensive analysis of the tannins' mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses.

Conclusions: CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.

Show MeSH
Related in: MedlinePlus