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Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.

Song JH, Kwon BE, Jang H, Kang H, Cho S, Park K, Ko HJ, Kim H - Biomol Ther (Seoul) (2015)

Bottom Line: We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity.Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels.Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.

ABSTRACT
Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

No MeSH data available.


Related in: MedlinePlus

The antiviral activity of 4-substituted benzyl chrysin derivatives 8–11 against CVB3. (A) Cytotoxicity and (B) antiviral activity of 8–11 against coxsackievirus B3 (CVB3) in Vero cells. Vero cells were infected with CVB3, after which they were treated with the indicated concentrations (0.4, 2, 10, and 50 μM) of 8–11 for 48 h. Antiviral activity was investigated using a cytopathic effect (CPE) reduction assay. Data are presented as means ± S.D. from three independent experiments each carried out in triplicate. (C) Morphological assessment of CVB3-infected Vero cells following treatment with 4-substituted benzyl derivatives of 7. (a) Non-infected cells; (b) non-infected cells treated with 9; (c) non-infected cells treated with 10; (d) non-infected cells treated with 11; (e) CVB3-infected cells; (f) CVB3-infected cells treated with 9; (g) CVB3-infected cells treated with 10; (h) CVB3-infected cells treated with 11.
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f3-bt-23-465: The antiviral activity of 4-substituted benzyl chrysin derivatives 8–11 against CVB3. (A) Cytotoxicity and (B) antiviral activity of 8–11 against coxsackievirus B3 (CVB3) in Vero cells. Vero cells were infected with CVB3, after which they were treated with the indicated concentrations (0.4, 2, 10, and 50 μM) of 8–11 for 48 h. Antiviral activity was investigated using a cytopathic effect (CPE) reduction assay. Data are presented as means ± S.D. from three independent experiments each carried out in triplicate. (C) Morphological assessment of CVB3-infected Vero cells following treatment with 4-substituted benzyl derivatives of 7. (a) Non-infected cells; (b) non-infected cells treated with 9; (c) non-infected cells treated with 10; (d) non-infected cells treated with 11; (e) CVB3-infected cells; (f) CVB3-infected cells treated with 9; (g) CVB3-infected cells treated with 10; (h) CVB3-infected cells treated with 11.

Mentions: Interestingly, among the four 4-substituted benzyl derivatives, 9–11 had significant antiviral activity at 50 μM. Especially, 9 showed significant antiviral activity even at 5 μM, without inducing cytotoxicity (Fig. 3A, B). In addition, we also checked the morphology of Vero cells infected with CVB3 after treatment with 9–11 using the SRB method. In the absence of infection of Vero cells with CVB3, cells treated with the vehicle or 10 μM of each compound showed typical spread-out shapes with normal morphology (Fig. 3C). Infection with CVB3 in the absence of drug treatment resulted in a severe CPE (Fig. 3C). On the contrary, the addition of 9, 10, and 11 to the Vero cells infected with CVB3 inhibited the formation of a visible CPE (Fig. 3C). Collectively, these results suggest that the 9–11 flavonoid derivatives have significant antiviral activity against CVB3 without inducing cytotoxicity in Vero cells.


Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.

Song JH, Kwon BE, Jang H, Kang H, Cho S, Park K, Ko HJ, Kim H - Biomol Ther (Seoul) (2015)

The antiviral activity of 4-substituted benzyl chrysin derivatives 8–11 against CVB3. (A) Cytotoxicity and (B) antiviral activity of 8–11 against coxsackievirus B3 (CVB3) in Vero cells. Vero cells were infected with CVB3, after which they were treated with the indicated concentrations (0.4, 2, 10, and 50 μM) of 8–11 for 48 h. Antiviral activity was investigated using a cytopathic effect (CPE) reduction assay. Data are presented as means ± S.D. from three independent experiments each carried out in triplicate. (C) Morphological assessment of CVB3-infected Vero cells following treatment with 4-substituted benzyl derivatives of 7. (a) Non-infected cells; (b) non-infected cells treated with 9; (c) non-infected cells treated with 10; (d) non-infected cells treated with 11; (e) CVB3-infected cells; (f) CVB3-infected cells treated with 9; (g) CVB3-infected cells treated with 10; (h) CVB3-infected cells treated with 11.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556207&req=5

f3-bt-23-465: The antiviral activity of 4-substituted benzyl chrysin derivatives 8–11 against CVB3. (A) Cytotoxicity and (B) antiviral activity of 8–11 against coxsackievirus B3 (CVB3) in Vero cells. Vero cells were infected with CVB3, after which they were treated with the indicated concentrations (0.4, 2, 10, and 50 μM) of 8–11 for 48 h. Antiviral activity was investigated using a cytopathic effect (CPE) reduction assay. Data are presented as means ± S.D. from three independent experiments each carried out in triplicate. (C) Morphological assessment of CVB3-infected Vero cells following treatment with 4-substituted benzyl derivatives of 7. (a) Non-infected cells; (b) non-infected cells treated with 9; (c) non-infected cells treated with 10; (d) non-infected cells treated with 11; (e) CVB3-infected cells; (f) CVB3-infected cells treated with 9; (g) CVB3-infected cells treated with 10; (h) CVB3-infected cells treated with 11.
Mentions: Interestingly, among the four 4-substituted benzyl derivatives, 9–11 had significant antiviral activity at 50 μM. Especially, 9 showed significant antiviral activity even at 5 μM, without inducing cytotoxicity (Fig. 3A, B). In addition, we also checked the morphology of Vero cells infected with CVB3 after treatment with 9–11 using the SRB method. In the absence of infection of Vero cells with CVB3, cells treated with the vehicle or 10 μM of each compound showed typical spread-out shapes with normal morphology (Fig. 3C). Infection with CVB3 in the absence of drug treatment resulted in a severe CPE (Fig. 3C). On the contrary, the addition of 9, 10, and 11 to the Vero cells infected with CVB3 inhibited the formation of a visible CPE (Fig. 3C). Collectively, these results suggest that the 9–11 flavonoid derivatives have significant antiviral activity against CVB3 without inducing cytotoxicity in Vero cells.

Bottom Line: We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity.Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels.Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.

ABSTRACT
Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

No MeSH data available.


Related in: MedlinePlus