Inhibitory Effects of Caffeic Acid Phenethyl Ester Derivatives on Replication of Hepatitis C Virus

Hui Shen,Tomohisa Tanaka,Hirotake Kasai,Hiromasa Yokoe,Yuusuke Fujimoto,Nobuyuki Enomoto,Masanori Ikeda,Masayoshi Tsubuki,Shinya Maekawa,Naoya Sakamoto,Atsuya Yamashita,Hiroko Shindo,Masamichi Nakakoshi,Masashi Sudo,Kohji Moriishi,Nobuyuki Kato,Hak Hotta

doi:10.1371/journal.pone.0082299

Abstract

Caffeic acid phenethyl ester (CAPE) has been reported as a multifunctional compound. In this report, we tested the effect of CAPE and its derivatives on hepatitis C virus (HCV) replication in order to develop an effective anti-HCV compound. CAPE and CAPE derivatives exhibited anti-HCV activity against an HCV replicon cell line of genotype 1b with EC50 values in a range from 1.0 to 109.6 µM. Analyses of chemical structure and antiviral activity suggested that the length of the n-alkyl side chain and catechol moiety are responsible for the anti-HCV activity of these compounds. Caffeic acid n-octyl ester exhibited the highest anti-HCV activity among the tested derivatives with an EC50 value of 1.0 µM and an SI value of 63.1 by using the replicon cell line derived from genotype 1b strain Con1. Treatment with caffeic acid n-octyl ester inhibited HCV replication of genotype 2a at a similar level to that of genotype 1b irrespectively of interferon signaling. Caffeic acid n-octyl ester could synergistically enhance the anti-HCV activities of interferon-alpha 2b, daclatasvir, and VX-222, but neither telaprevir nor danoprevir. These results suggest that caffeic acid n-octyl ester is a potential candidate for novel anti-HCV chemotherapy drugs.

Highlights

Hepatitis C virus (HCV) is well known as a major causative agent of chronic liver disease including cirrhosis and hepatocellular carcinoma and is thought to persistently infect 170 million patients worldwide [1]
We examined the effect of Caffeic acid phenethyl ester (CAPE) on both viral replication and cell growth in the HCV subgenomic replicon cell line Huh7/Rep-Feo
Based on the calculation using a dose dependency of CAPE, compound 1 exhibited an EC50 value of 9.0 mM and a CC50 value of 136.1 mM, giving a selectivity index estimate (SI) of 17.9 (Table 1). These results suggest that treatment with CAPE inhibits HCV replication in HCV subgenomic replicon cells

Summary

Introduction

Hepatitis C virus (HCV) is well known as a major causative agent of chronic liver disease including cirrhosis and hepatocellular carcinoma and is thought to persistently infect 170 million patients worldwide [1]. The single polypeptide coded by the genome is composed of 3,000 amino acids and is cleaved by host and viral proteases, resulting in 10 proteins, which are classified into structural and nonstructural proteins [3]. The advanced NS3/4A protease inhibitors, telaprevir and boceprevir, have been employed in the treatment of chronic hepatitis C patients infected with genotype 1 [5]. Sustained virologic response (SVR) was reportedly 80% in patients infected with genotype 1 following triple combination therapy with pegylated interferon, ribavirin, and telaprevir [6], the therapy exhibits side effects including rash, severe cutaneous eruption, influenza-like symptoms, cytopenias, depression, and anemia [7]. There is the possibility of the emergence of drug-resistant viruses following treatment with those anti-HCV drugs [8] further study is required for development of safer and more effective anti-HCV compounds

Methods

Results

Conclusion