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

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.

Inhibition Mechanisms of Hepatitis C Virus Infection by Caffeic Acid and Tannic Acid

“…Recently, it was reported that CA prevented HCV genome replication, 13,14) but we did not observe this effect in the present study (Fig. 2).…”

“…This might be explained by differences in researchers' use of host cells and viral/replicon strains. In the present study, we used Huh7.5.1-8 cells and HCV-JFH1 (genotype 2a), while previous studies have used Huh7, 13,14) Huh7.5.1, 13) Con1 replicon (genotype 1b), J399EM (genotype 2a), a JFH-1-based adaptive strain in which an enhanced green fluorescent protein (EGFP) gene was inserted into NS5A, 13) and N replicon (genotype 1b). 15) It has also been reported that CA has inhibitory effects on other viruses such as hepatitis B virus (HBV), canine distemper virus (CDV), herpes simplex virus type 1 (HSV-1), influenza A virus (IAV), polio virus type 1 (PV-1), and severe fever with thrombocytopenia syndrome virus (SFTSV) in cultured cells.…”

“…15) It has also been reported that CA has inhibitory effects on other viruses such as hepatitis B virus (HBV), canine distemper virus (CDV), herpes simplex virus type 1 (HSV-1), influenza A virus (IAV), polio virus type 1 (PV-1), and severe fever with thrombocytopenia syndrome virus (SFTSV) in cultured cells. 12,[14][15][16][17]19,21,39) CA has also shown inhibitory activity against human immunodeficiency virus (HIV) integrase (IC 50 = 2.8 µM), 20,40) which is a critical enzyme for HIV replication. HBV infection was prevented by CA mainly at the viral genome replication step.…”

“…It has many beneficial biological effects, including inhibition of cancer cell proliferation and metastasis 9,10) and antiviral activities against a variety of viruses. [11][12][13][14][15][16][17][18][19][20][21] Previously, our group has shown that CA inhibits HCV infection and HCV entry into cells, 11) but the detailed antiviral mechanism has not yet been defined. In the present study, we investigated the inhibitory effect of another coffee-related compound, tannic acid (TA), on HCV infection and further examined how CA and TA inhibit HCV infection.…”

Caffeic acid phenethyl ester (CAPE) revisited: Covalent modulation of XPO1/CRM1 activities and implication for its mechanism of action

“…To date, a broad spectrum of biological properties in addition to antitumor and anti‐inflammatory activities has been reported for CAPE. For example, CAPE was recently reported with inhibitory effects on replication of hepatitis C virus . We believe that the inhibition of nuclear export by CAPE is a rather reasonable explanation for its various biological activities.…”