Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication
Eunhyun Ryu1,*, Myoungki Son1,*, Minjung Lee1, Kanghyo Lee2, Jae Youl Cho3, Sungchan Cho4, Suk Kyeong Lee5, You Mie Lee1, Hyosun Cho6, Gi-Ho Sung7 and Hyojeung Kang1
1 College of Pharmacy and Institute of microorganisms, Kyungpook National University, Daegu, Republic of Korea
2 Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Republic of Korea
3 Department of Genetic Engineering, Sungkyunkwan University, Suwon, Republic of Korea
4 Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Chungbuk, Republic of Korea
5 Research Institute of Immunobiology, Department of Biomedical Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
6 College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea
7 Institute for Bio-Medical Convergence, International St. Mary’s Hospital, College of Medicine, Catholic Kwangdong University, Incheon, Republic of Korea
* These authors contributed equally to this work
Correspondence:
Hyojeung Kang, email:
Gi-Ho Sung, email:
Hyosun Cho, email:
Keywords: Cordycepin, Epstein–Barr virus, gastric carcinoma, antiviral agent
Received: November 27, 2014 Accepted: December 14, 2014 Published: December 18, 2014
Abstract
Cordyceps species are known to produce numerous active components and are used for diverse medicinal purposes because of their varied physiological activities, including their ability to protect the liver from damage as well as their anticancer, antidepressant, anti-inflammatory, hypoglycemic, antimicrobial effects. Cordycepin, an adenosine derivative, differs from adenosine in that its ribose lacks an oxygen atom at the 3′ position. Several research groups have reported that cordycepin has antiviral activity against several viruses including influenza virus, plant viruses, human immunodeficiency virus(HIV), murine leukemia virus, and Epstein-Barr virus (EBV). In this study, we identify the epigenetic mechanisms by which cordycepin exerts its anti-gammaherpesvirus effects. We show that cordycepin possesses antitumor and antiviral activity against gastric carcinoma and EBV, respectively. A comparison of the CD50 values of cordycepin and its analogs showed that the lack of a 2′-hydroxyl group in cordycepin was critical for its relatively potent cytotoxicity. Cordycepin treatment decreased the rate of early apoptosis in SNU719 cells by up to 64%, but increased late apoptosis/necrosis by up to 31%. Interestingly, cordycepin increased BCL7A methylation in SNU719 cells by up to 58% and decreased demethylation by up to 37%. Consistent with these changes in methylation, cordycepin treatment significantly downregulated most EBV genes tested. Under the same conditions, cordycepin significantly decreased the frequency of Qp and Fp promoter usage, and H3K4me3 histone enrichment was significantly reduced at several important EBV genomic loci. Extracellular and intracellular EBV genome copy numbers were reduced by up to 55% and 30%, respectively, in response to 125 µM cordycepin treatment.
Finally, cordycepin significantly suppressed the transfer of EBV from LCL-EBV-GFP to AGS cells, indicating that EBV infection of gastric epithelial cells was inhibited. These results suggest that cordycepin has antiviral and antitumor activities against gammaherpesviruses and host cells latently infected with virus.
