Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.
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.
Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.
Jae-Hyoung
JH
Song
Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.
Bo-Eun
BE
Kwon
College of Pharmacy, Ajou University, Suwon 443-749.
Hongjun
H
Jang
Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 363-883.
Hyunju
H
Kang
Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 363-883.
Sungchan
S
Cho
Department of Microbiology, Chungcheongnam-Do Institute of Health and Environmental Research, Daejeon 300-801, Republic of Korea.
Kwisung
K
Park
Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.
Hyun-Jeong
HJ
Ko
College of Pharmacy, Ajou University, Suwon 443-749.
Hyoungsu
H
Kim
Antiviral activity; Chrysin; Coxsackievirus B3; Flavonoid; Pancreatitis