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Functional foods effective for hepatitis C: Identification of oligomeric proanthocyanidin and its action mechanism

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Hepatitis C virus (HCV) is a major cause of viral hepatitis and currently infects approximately 170 million people worldwide. An infection by HCV causes high rates of chronic hepatitis (> 75%) and progresses to liver cirrhosis and hepatocellular carcinoma ultimately. HCV can be eliminated by a combination of pegylated α-interferon and the broad-spectrum antiviral drug ribavirin; however, this treatment is still associated with poor efficacy and tolerability and is often accompanied by serious side-effects. While some novel direct-acting antivirals against HCV have been developed recently, high medical costs limit the access to the therapy in cost-sensitive countries. To search for new natural anti-HCV agents, we screened local agricultural products for their suppressive activities against HCV replication using the HCV replicon cell system in vitro. We found a potent inhibitor of HCV RNA expression in the extracts of blueberry leaves and then identified oligomeric proanthocyanidin as the active ingredient. Further investigations into the action mechanism of oligomeric proanthocyanidin suggested that it is an inhibitor of heterogeneous nuclear ribonucleoproteins (hnRNPs) such as hnRNP A2/B1. In this review, we presented an overview of functional foods and ingredients efficient for HCV infection, the chemical structural characteristics of oligomeric proanthocyanidin, and its action mechanism.
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World Journal of
Hepatology
World J Hepatol 2014 December 27; 6(12): 830-938
Published by Baishideng Publishing Group Inc
ISSN 1948-5182 (online)
Contents Monthly Volume 6 Number 12 December 27, 2014
December 27, 2014
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Volume 6
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Issue 12
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WJH
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www.wjgnet.com I
830 Role of anti-angiogenesis therapy in the management of hepatocellular
carcinoma: The jury is still out
Sun H, Zhu MS, Wu WR, Shi XD, Xu LB
836 Role of hepatectomy for recurrent or initially unresectable hepatocellular
carcinoma
Kishi Y, Shimada K, Nara S, Esaki M, Kosuge T
844 Transarterial chemoembolization for hepatocellular carcinoma: A review of
techniques
Imai N, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Goto H
851 How did hepatitis B virus effect the host genome in the last decade?
Ozkal-Baydin P
860 Occult hepatitis B virus infection
Kwak MS, Kim YJ
870 Functional foods effective for hepatitis C: Identification of oligomeric
proanthocyanidin and its action mechanism
Ishida Y, Takeshita M, Kataoka H
880 Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis:
Novel treatment strategies
Takeuchi M, Takino J, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, Hyogo H,
Yamagishi S
894 Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver
disease during the last three decades
Ikura Y
901 Vitamin D deficiency in chronic liver disease
Iruzubieta P, Terán Á, Crespo J, Fábrega E
916 Recombinase polymerase amplification as a promising tool in hepatitis C virus
diagnosis
Zaghloul H, El-shahat M
TOPIC HIGHLIGHT
REVIEW
MINIREVIEWS
Contents World Journal of Hepatology
Volume 6 Number 12 December 27, 2014
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923 Palliative external-beam radiotherapy for bone metastases from hepatocellular
carcinoma
Hayashi S, Tanaka H, Hoshi H
930 Evaluation of hepatocellular carcinoma development in patients with chronic
hepatitis C by EOB-MRI
Nojiri S, Fujiwara K, Shinkai N, Endo M, Joh T
RETROSPECTIVE
STUDY
Contents World Journal of Hepatology
Volume 6 Number 12 December 27, 2014
FLYLEAF
EDITORS FOR
THIS ISSUE
Responsible Assistant Editor: Xiang Li Responsible Science Editor: Fang-Fang Ji
Responsible Electronic Editor: Su-Qing Liu Proong Editorial Ofce Director: Xiu-Xia Song
Proong Editor-in-Chief: Lian-Sheng Ma
NAME OF JOURNAL
World Journal of Hepatology
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ISSN 1948-5182 (online)
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October 31, 2009
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APPENDIX
ABOUT COVER
AIM AND SCOPE
I-V Instructions to authors
Editorial Board Member of
World Journal of Hepatology
, Roberto J Carvalho-
Filho, MD, PhD, Professor, Division of Gastroenterology, Hepatology Section,
Federal University of Sao Paulo, Sao Paulo, Sao Paulo 04023-060, Brazil
World Journal of Hepatology (World J Hepatol, WJH, online ISSN 1948-5182, DOI:
10.4254), is a peer-reviewed open access academic journal that aims to guide clinical
practice and improve diagnostic and therapeutic skills of clinicians.
WJH covers topics concerning arrhythmia, heart failure, vascular disease, stroke,
hypertension, prevention and epidemiology, dyslipidemia and metabolic disorders,
cardiac imaging, pediatrics, nursing, and health promotion. Priority publication will
be given to articles concerning diagnosis and treatment of hepatology diseases. The
following aspects are covered: Clinical diagnosis, laboratory diagnosis, differential
diagno sis, imaging tests, pathological di agnosis, molecular biological diagnosis,
immunological diagnosis, genetic diagnosis, functional diagnostics, and physical
diagnosis; and comprehensive therapy, drug therapy, surgical therapy, interventional
treatment, minimally invasive therapy, and robot-assisted therapy.
We encourage authors to submit their manuscripts to WJH. We will give priority
to manuscripts that are supported by major national and international foundations and
those that are of great basic and clinical signicance.
World Journal of Hepatology is now indexed in PubMed Central, PubMed, Digital Object
Identier, Directory of Open Access Journals, and Scopus.
I-IV Editorial Board
INDEXING/
ABSTRACTING
Yo-ichi Ishida, Masahiko Takeshita, Hiroaki Kataoka
Yo-ichi Ishida, Department of Molecular and Cellular Biochem-
istry, Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588,
Japan
Masahiko Takeshita, Research Division, Minami Nippon Dairy
Co-op., Ltd., Miyakonojo, Miyazaki 885-0003, Japan
Hiroaki Kataoka, Section of Oncopathology and Regenerative
Biology, Department of Pathology, Faculty of Medicine, Univer-
sity of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
Author contributions: Ishida Y contributed to the investigation
of the action mechanism of oligomeric proanthocyanidin, drafting
of the manuscript, and literature review; Takeshita M contributed
to the discovery of oligomeric proanthocyanidin as an anti-HCV
agent and approved the final version of this manuscript; Kataoka
H contributed to the management of the study, critically reviewed
and approved the final version of this manuscript.
Supported by The Collaboration of Regional Entities for the
Advancement of Technological Excellence from Japan Science
and Technology Agency
Correspondence to: Hiroaki Kataoka, MD, PhD, Professor,
Section of Oncopathology and Regenerative Biology, Department
of Pathology, Faculty of Medicine, University of Miyazaki, 5200
Kihara, Kiyotake, Miyazaki 889-1692,
Japan. mejina@med.miyazaki-u.ac.jp
Telephone: +81-985-852809 Fax: +81-985-856003
Received: August 26, 2014 Revised: October 3, 2014
Accepted: October 23, 2014
Published online: December 27, 2014
Abstract
Hepatitis C virus (HCV) is a major cause of viral hepa-
titis and currently infects approximately 170 million
people worldwide. An infection by HCV causes high
rates of chronic hepatitis (> 75%) and progresses to
liver cirrhosis and hepatocellular carcinoma ultimately.
HCV can be eliminated by a combination of pegylated
α-interferon and the broad-spectrum antiviral drug rib-
avirin; however, this treatment is still associated with
poor efficacy and tolerability and is often accompanied
by serious side-effects. While some novel direct-acting
antivirals against HCV have been developed recently,
high medical costs limit the access to the therapy in
cost-sensitive countries. To search for new natural an-
ti-HCV agents, we screened local agricultural products
for their suppressive activities against HCV replication
using the HCV replicon cell system
in vitro
. We found a
potent inhibitor of HCV RNA expression in the extracts
of blueberry leaves and then identified oligomeric
proanthocyanidin as the active ingredient. Further in-
vestigations into the action mechanism of oligomeric
proanthocyanidin suggested that it is an inhibitor of
heterogeneous nuclear ribonucleoproteins (hnRNPs)
such as hnRNP A2/B1. In this review, we presented an
overview of functional foods and ingredients efficient
for HCV infection, the chemical structural character-
istics of oligomeric proanthocyanidin, and its action
mechanism.
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Key words: Hepatitis C virus; Blueberry leaves; Func-
tional foods; Oligomeric proanthocyanidin; Heteroge-
neous nuclear ribonucleoproteins
Core tip: An infection by hepatitis C virus (HCV) causes
chronic hepatitis, liver cirrhosis, and hepatocellu-
lar carcinoma. While the combination of pegylated
α-interferon and ribavirin is used for the elimination of
HCV, a new anti-HCV drug is required due to the poor
efficacy and serious side-effects associated with this
combination therapy. We searched for new anti-HCV
agents from natural products and then identified oligo-
meric proanthocyanidin from blueberry leaves. Further
investigations suggested that several heterogeneous
nuclear ribonucleoproteins may be the candidate pro-
teins involved in the proanthocyanidin-mediated inhibi-
tion of HCV subgenomic expression. Oligomeric proan-
thocyanidin isolated from blueberry leaves may have
potential usefulness as an anti-HCV compound.
TOPIC HIGHLIGHT
Submit a Manuscript: http://www.wjgnet.com/esps/
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx
DOI: 10.4254/wjh.v6.i12.870
870 December 27, 2014
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World J Hepatol 2014 December 27; 6(12): 870-879
ISSN 1948-5182 (online)
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Functional foods effective for hepatitis C: Identification of
oligomeric proanthocyanidin and its action mechanism
WJH 6th Anniversary Special Issues (5): Hepatitis C virus
Ishida Y, Takeshita M, Kataoka H. Functional foods effective for
hepatitis C: Identification of oligomeric proanthocyanidin and its
action mechanism. World J Hepatol
2014; 6(12): 870-879 Avail-
able from: URL: http://www.wjgnet.com/1948-5182/full/v6/
i12/870.htm DOI: http://dx.doi.org/10.4254/wjh.v6.i12.870
INTRODUCTION
Hepatitis C virus (HCV) is a major cause of viral hepati-
tis and currently infects approximately 170 million people
worldwide[1,2]. An infection by HCV causes high rates of
chronic hepatitis (> 75%) and progresses to liver cirrhosis
and hepatocellular carcinoma ultimately[3]. A total of 27%
and 25% of individuals that develop liver cirrhosis and
hepatocellular carcinoma worldwide, respectively, arise in
HCV-infected people[4]. The World Health Organization
reported that between 350000 and 500000 people die
from HCV-related diseases each year. However, there is
no effective vaccine against HCV infection at present.
Currently, the combination of pegylated α-interferon
and a broad spectrum antiviral drug, ribavirin, is used
as the standard therapy for chronic HCV infection[2,5,6] .
However, its option is unfortunately limited by efcacy,
tolerability, and signicant side-effects. Therefore, it had
been required to establish a new therapeutic modality
without serious adverse effects. Recently, direct-acting
antivirals (DAAs) that inhibit HCV-specic proteins have
be clinically investigated[7,8]. For example, boceprevir and
telaprevir are new DAAs that were rst approved by the
United States Food and Drug Administration (FDA) in
2011[9]. DAAs are expected to provide new promising
treatment options in hepatitis C patients; however, at
present, they face difficulties to disseminate worldwide
due to high costs. Therefore, new anti-HCV agents that
are safe, economical, and complementary with present
therapies, are still required.
Since the development of HCV-related liver cirrhosis
and hepatocellular carcinoma requires a prolonged period
(20-30 years), the progression of this disease may be inu-
enced by a diet including dairy products. Interest in func-
tional foods and their ingredients as natural resources for
cancer prevention and treatment is increasing[10,11]. Eating
habits, foods, nutrients contained in them, and other food
constituents play important roles on the development
of several types of cancer and 35% of cancer deaths are
estimated to be possibly related to dietary factors[12]. Poly-
phenols derived from various fruits and vegetables have
recently been suggested to be effective in the prevention
of cancer. The South Kyushu region of Japan, including
the prefecture of Miyazaki, has been recognized as a high
prevalence area of HCV and it emerges as a social issue.
Therefore, attempts were made to identify functional food
ingredients having suppressive activities against HCV rep-
lication as an industry-academia-government collabora-
tion study[13]. By screening of 1700 samples from 283 ag-
ricultural products in Miyazaki prefecture, we found that
oligomeric proanthocyanidin, a polyphenolic ingredient
abundantly contained in the leaves of the blueberry plant,
suppressed the expression of HCV subgenomic RNA in
an HCV replicon cell system[13].
In this review, we presented an overview of func-
tional foods and ingredients efcient for HCV infection,
the chemical structural characteristics of oligomeric pro-
anthocyanidin, and its action mechanism.
HCV LIFE CYCLE AND ANALYTICAL
TOOL
HCV belongs to Hepacivirus genus of the Flaviviridae fam-
ily and has a positive-sense single stranded RNA of 9.6
kb wrapped with enveloped membrane[14]. After their ad-
sorption on the surface of host cells, HCV particles are
internalized into endocytic compartments and viral ge-
nomic RNA is then released into the cytoplasm by fusion
of the viral envelope and cellular membrane. Genomic
RNA serves as mRNA for viral proteins and is translated
into a single polyprotein (3011 amino acids), resulting in
4 structural proteins (Core, E1, E2, and p7) and 6 non-
structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A,
and NS5B) by post-translational processing (Figure 1A).
It also serves as a template for viral genome replication.
Non-translated regions (NTRs), 5’NTR and 3’NTR, are
connected with the HCV polyprotein-coding region, and
modulate viral protein synthesis and genome replication.
The assembly of these viral components occurs on the
endoplasmic reticulum (ER) membrane. Viral proteins
and genomic RNA assemble on the cytoplasmic side of
the membrane and then progeny virions bud into the ER
lumen, followed by their release to the extracellular space.
In the life cycle of HCV, each viral protein functions as
described below[14]. Core is a highly basic protein that
encapsidates HCV genomic RNA. E1 and E2 are glyco-
proteins integrated into the viral envelope. p7 functions
as an ion channel and an antiviral drug, amantadine, is the
p7 ion channel blocker[15]. Importantly, several steps of
HCV infectious process are coordinated by NS proteins.
NS2 and NS3 are a cysteine protease and serine prote-
ase, respectively, that play roles in the post-translational
processing of viral proteins. NS3 serine protease activity
requires NS4A as a cofactor. NS4B and NS5A have been
suggested to serve in viral assembly on the ER membrane
and NS5B is an RNA-dependent RNA polymerase. Many
studies to date have reported that these viral proteins are
associated not only with viral replication, but also patho-
genicity via interactions with various host proteins. The
identication of host proteins associated with the HCV
life cycle is very important for anti-HCV drugs, and the
HCV replicon cell system has contributed significantly
to the development of these drugs[16,17]. This system con-
sists of the human hepatocellular carcinoma line Huh-7
in which the transfected luciferase gene connected with
HCV subgenomic RNA including the downstream cod-
ing regions of NS3 and the expression of HCV subge-
nomic RNA can be quantied by luciferase activity (Figure
1B). It provides a useful tool for HCV drug development
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Ishida Y
et al
. Oligomeric proanthocyanidin suppresses HCV subgenomic replication
and the elucidation of mechanisms underlying HCV
genome replication[17]. We have used this HCV replicon
system to screen functional foods with anti-HCV activity.
THERAPEUTIC OPTIONS FOR CHRONIC
HCV INFECTION
Currently, the combination of pegylated α-interferon and
a broad spectrum antiviral drug, ribavirin, is used as the
standard therapy for chronic HCV infection[2,5,6]. How-
ever, the HCV genotype is an important determinant of
its efficacy and tolerability. Whereas the virological re-
sponse to this combination therapy is more than 70% for
genotypes 2 and 3, it is less than 50% for genotype 1[18-20].
Furthermore, this therapy causes signicant side-effects
such as thrombocytopenia, u-like symptoms, fever, rash,
anorexia, and thyroid dysfunction. Depression and irrita-
bility that are expressed as neuropsychological disorders
during therapy impair quality of life universally. There-
fore, it had been required to establish a new therapeutic
modality without serious adverse effects.
Recently, DAAs that inhibit HCV-specific proteins
have been clinically investigated[7,8]. Two DAAs, bocepre-
vir and telaprevir first came to the HCV drug market
and were approved by FDA in May 2011. Boceprevir
or telaprevir was used as triple therapy with pegylated
α-interferon and ribavirin for hepatitis C patients with
genotype 1[9]. These DAAs are inhibitors against HCV
NS3/4A serine protease and bind covalently with active
site of the enzyme[21-23]. The triple therapy using bocepre-
vir or telaprevir significantly increased the rate of sus-
tained virological response (SVR) for naive or previous
treated hepatitis C patients with HCV genotype 1[24-29].
After that, next generation DAAs, ABT-450/r, simepre-
vir, and faldaprevir, which are also NS3/4A protease
inhibitors, have been reported to have advantages of
their convenience and improved side effects prole[30-32].
Further, daclatasvir and sofosbuvir, which are an NS5A
replication complex inhibitor and a nucleotide analogue
NS5B polymerase inhibitor, respectively, also increased
SVR rate[33-35]. Notably, the combination of these DAAs
only was the highly effective treatment for patients with
HCV genotype 1[36,37] and it is feasible to treat HCV with-
out interferon and ribavirin.
While patients with hepatitis C can be treated by
above mentioned DAAs without signicant side-effects,
it requires high medical costs and limits access to the
therapy in cost-sensitive countries[38]. Of the 20 countries
with the high prevalence of HCV, 12 are categorized as
low or lower-middle income countries[39]. Therefore, new
anti-HCV agents that are safe, economical, and comple-
mentary with present therapies, are still required and we
focus attention on functional foods and their ingredients.
FUNCTIONAL FOOD INGREDIENTS
EFFECTIVE FOR HCV
The development of HCV-related liver cirrhosis and
hepatocellular carcinoma requires a prolonged period
(20-30 years). Therefore, the progression of the disease
and HCV infectivity may be inuenced by a diet includ-
ing dairy products. Functional foods and their ingredients
are known to be capable of modulating various biologi-
cal processes such as apoptosis and have been attracting
interest as natural resources for the prevention and treat-
ment of cancer[10,11,40]. Dietary polyphenols derived from
various fruits and vegetables have been suggested to be
effective in cancer prevention. Although the importance
of functional food ingredients as DAAs against HCV is
not fully recognized, these ndings suggest that they con-
tribute to the elimination of the virus.
Several functional food ingredients have been re-
ported to interfere with different steps of the HCV life
cycle. Epigallocatechin-3-gallate (EGCG) (Figure 2A) and
curcumin (Figure 2B), which are ingredients of green tea
(Camellia sinensis) and the Indian spice turmeric (Cur-
cuma longa), respectively, inhibit the entry of HCV into
host cells[41,42]. Quercetin (Figure 2C), a flavonoid that
is abundantly contained in onions, apples, berries, and
red wine, has been shown to inhibit NS3 protease activ-
ity[43]. Punicalagin (Figure 2D) and its related substance
punicalin from the pomegranate (Punica granatum L.) re-
duced the replication of HCV[44]. Naringenin (Figure 2E)
from the grapefruit (Citrus X paradisi Macfady.) has been
identified as an ingredient that interferes with viral as-
sembly[45,46]. Diosgenin (Figure 2F) and epicatechin (Figure
2G), which are contained in yams (Dioscorea spp.) and
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HCV genomic RNA
5’NTR 3’NTR
Polyprotein-coding region
Translation
Polyprotein (3011 amino acids)
Structural proteins
Post-translational processing
Nonstructural proteins
Core p7 NS4BNS4A
NS2 NS3 NS5A NS5BE1 E2
5’NTR 3’NTR
Luciferase NS3
NS4A NS4B
NS5A NS5B
B
A
Figure 1 Structure of the hepatitis C virus genome and cell system for an-
ti-hepatitis C virus drug discovery. A: HCV genomic RNA and viral proteins.
HCV genomic RNA encodes a single polyprotein of 3011 amino acids. After
being translated, the polyprotein is processed into 4 structural proteins (Core,
E1, E2, and p7) and 6 non-structural (NS) proteins (NS2, NS3, NS4A, NS4B,
NS5A, and NS5B). The polyprotein-coding region is anked by 5’ and 3’NTRs.
Viral RNA also serves as a template for viral genome replication and both NTRs
modulate viral protein synthesis and genome replication; B: The HCV replicon
cell system. Huh-7 cells were transfected with the luciferase gene connected
with HCV subgenomic RNA including the downstream coding regions of NS3.
The expression of HCV subgenomic RNA could be quantied by luciferase ac-
tivity. HCV: Hepatitis C virus; NTRs: Non-translated regions.
Ishida Y
et al
. Oligomeric proanthocyanidin suppresses HCV subgenomic replication
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anum) and consists of at least 7 flavonoid compounds,
was also found to interfere with several steps of HCV
infectious process, such as NS5B polymerase activity and
virus entry and transmission[51]. As shown in Figure 2,
most ingredients are polyphenol compounds and, EGCG
(A), quercetin (C), naringenin (E), and epicatechin (G)
have similar chemical structures. There may be a charac-
teristic structure modulating viral proteins and their asso-
ciations with host proteins.
green tea, respectively, also affect the signal transduction
pathways of host cells and inhibit HCV replication via
the signal transducer and activator of transcription 3 and
cycloxygenase-2 pathways, respectively[47,48]. The finding
that curcumin and quercetin also inhibited HCV replica-
tion by associating with sterol regulatory element binding
protein-1 and heat shock proteins, respectively, indicated
the existence of multifunctional ingredients[49,50]. Silyma-
rin, which is an extract from milk thistle (Silybum mari-
Figure 2 Chemical structure of functional food ingredients with anti-hepatitis C virus activities. A: Epigallocatechin-3-gallate; B: Curcumin; C: Quercetin; D:
Punicalagin; E: Naringenin; F: Diosgenin; G: (-)-epicatechin.
Ishida Y
et al
. Oligomeric proanthocyanidin suppresses HCV subgenomic replication
CH3
CH3
O
O
O
O
HO OH
OH
OH
OH
OH
HO O
O
HO
HO
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
OH
OH
O
O
OH
OH
OH
OH
HO O
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CH3
CH3
O
O
CH3
H
H
H
H
H
A B
C
D E
F G
HO
OH
O
OH
OH
OH
OH
OH
OH
O
O
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Clinically, the supplementation of vitamin group has
been reported to increase SVR rates in chronic hepatitis
C patients who underwent the standard therapy with
pegylated α-interferon and ribavirin[52-54]. Regarding sig-
nificant side-effects of the standard therapy, a tomato-
based functional food abundant in natural antioxidants
alleviated the severity of anemia caused by ribavirin and
improved the tolerance to the drug[55].
OLIGOMERIC PROANTHOCYANIDIN
FROM BLUEBERRY LEAVES HAS
SUPPRESSIVE ACTIVITY AGAINST HCV
SUBGENOME REPLICATION IN VITRO
To identify functional food ingredients effective for
hepatitis C, we comprehensively screened the extracts of
commonly ingested agricultural products (1700 samples
from 283 species) grown in Miyazaki prefecture, Japan
using an HCV replicon cell system[13 ]. Samples having
high antioxidative activities were rst selected irrespective
of edible part or non-edible part, and then the inhibitory
activities against HCV subgenomic RNA replication were
examined using the system. We found that extracts of
blueberry leaves signicantly suppressed the replication.
Furthermore, by comparing the inhibitory activities us-
ing leaves from various kinds of blueberry species, it was
found that the leaves of rabbit-eye blueberry (Vaccinium
virgatum Aiton) had the highest activity[13]. Rabbit-eye
blueberry is cultivated in a region with a warm climate,
such as the southern areas of Japan, including Miyazaki
prefecture. Its leaves have been also reported to be good
sources of polyphenols and natural antioxidants[56].
We identified oligomeric proanthocyanidin as the
blueberry leaf-derived inhibitor of HCV subgenomic
RNA replication[13]. Proanthocyanidin is a polyphenol
and has polymerized structures in which more than two
avan-3-ol units such as catechin (Figure 3A) and epicat-
echin (Figure 2G) are covalently linked. Figure 3B shows
an example of the chemical structure of proanthocyani-
din. Proanthocyanidin possesses two interflavan bonds,
in which the A-type and B-type have two bond linkages
(C4→C8 and O7→C2) and one linkage (C4→C8 or C4
→C6), respectively[57], and both types co-exist in proan-
thocyanidin from the rabbit-eye blueberry plant[13]. While
catechin, epicatechin, EGCG, and dimers such as procy-
anidin B2 did not exhibit inhibitory activity against HCV
subgenomic expression in our experimental system, pro-
anthocyanidin oligomer having polymerization degree of
8 to 9 markedly inhibited this expression[13]. This nding
suggested that the HCV inhibitory activity of oligomeric
proanthocyanidin in the replicon assay may require an
oligomerized structure.
Proanthocyanidins are abundantly contained in vari-
ous plants and foods[58] and contribute to organoleptic
properties such as bitterness and astringency[59]. Proan-
thocyanidin-containing foods and nutritional supplements
are known to have benets in health promotion. United
States Department of Agriculture Database reported
proanthocyanidin contents of various foods, showing
that apple peel, red kidney beans, pinto beans, cacao
beans, cocoa, grape seeds, several nuts (almonds, hazel-
nuts, pecans, and pistachios), sorghum, and cinnamon are
proanthocyanidin-rich[60]. Blueberry fruits are also rela-
tively proanthocyanidin-rich; however, the fruits did not
show signicant HCV inhibitory activity compared to the
leaves (unpublished data). In the fruits, proanthocyanidin
contents of monomer, dimer, trimer, 4-6mer, 7-10mer,
and polymer with degrees of polymerization greater than
10mer are 3.46, 5.71, 4.15, 19.57, 14.55, and 129.05 mg
per 100 g edible portion, respectively[60]. As the inhibitory
activity required the oligomeric structure of proanthocy-
anidin having a polymerization degree of 8 to 9 but not
polymer and fresh blueberry leaf contained 3000-4000
mg proanthocyanidins per 100 g total extracts[13], leaves
but not fruits from blueberry are likely suitable for the
prevention of HCV-related diseases. With regard to the
oral uptake, oligomeric proanthocyanidin seems to elute
off by boiling for cooking as shown with pint beans[60].
Therefore, oligomeric proanthocyanidin from blueberry
HO
OH
OH
OH
OH
O
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
O
O
1
2
3
4
5
6
7
8
9
10
8
n
A
B
Figure 3 Chemical structures of a avan-3-ol and proanthocyanidin. A:
(+)-catechin; B: An example of a procyanidin B-type polymer with an (-)-epicat-
echin based structure.
Ishida Y
et al
. Oligomeric proanthocyanidin suppresses HCV subgenomic replication
875 December 27, 2014
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leaves might be ingested as a hot water extract such as
herbal tea. However, absorption efciency of oligomeric
proanthocyanidin in the intestine may be very low.
Proanthocyanidin has also been reported to possess
anti-viral activity against other viruses, herpes simplex
virus and human immunodeciency virus type 1[61-65]. To
the best of our knowledge, we rst reported that the pro-
anthocyanidin oligomer inhibited the expression of HCV
subgenomic RNA[13]. However, the effects of oligomeric
proanthocyanidin on HCV replication in hepatocytes in
vivo currently remain unknown.
ACTION MECHANISM OF OLIGOMERIC
PROANTHOCYANIDIN IN HCV REPLICON
CELLS
The suppression of HCV subgenomic RNA replica-
tion by oligomeric proanthocyanidin has been attracting
increasing attention. Polyphenolic compounds gener-
ally have high antioxidant activities[10,11,58]. Therefore,
the nonspecic antioxidant activity of polyphenols may
contribute to the suppression of HCV subgenomic RNA
replication by oligomeric proanthocyanidin. However, we
examined other polyphenolic compounds in our HCV
replicon assay, and found that constitutional units such
as catechin and epicatechin did not display suppressive
activity, which requires the oligomerized structure of
proanthocyanidin[13]. While it currently remains unknown
whether proanthocyanidin oligomer can be translocated
within the cells in spite of the structure, the ingredient
has been reported to be absorbed from the digestive
tract[66,67], implying the internalization into cells. Oligo-
meric proanthocyanidin appears to suppress HCV sub-
genomic RNA replication via a specic association with
certain intracellular molecules.
Proteomic approach using two-dimensional differen-
tial gel electrophoresis combined with mass spectrometry
provides a powerful tool to determine the cellular re-
sponse to functional foods[40]. To clarify the action mech-
anism of oligomeric proanthocyanidin in HCV replicon
cells, we performed proteomic analysis of proanthocy-
anidin-binding proteins puried by afnity chromatogra-
phy[13]. Then, cellular proteins from replicon cells having
higher affinity to proanthocyanidin than catechin were
identied by a mass spectrometric analysis, and whether
the proteins identied were associated with HCV RNA
expression was further examined using a siRNA-based
replicon assay (Figure 4). Four heterogeneous nuclear
ribonucleoproteins (hnRNPs), hnRNP A/B, A2/B1, K,
and L, were suggested to be possible cellular binding
proteins of oligomeric proanthocyanidin. While siRNA
targeting hnRNP A/B, K, and L showed weak inhibitory
activities, the knockdown of hnRNP A2/B1 signicantly
suppressed HCV subgenomic replication[13].
HnRNPs comprise a family of RNA-binding proteins
that are involved in diverse RNA-related biological pro-
cesses[68]. They are multifunctional proteins composed
of major and minor hnRNP proteins, and hnRNP A/B,
A2/B1, K, and L that we identified belonged to the
major hnRNPs[69]. Previous studies demonstrated that
these hnRNPs regulated the metabolism of RNA such as
pre-mRNA splicing and transcription[70-76]. For example,
hnRNP A2/B1 was shown to affect the alternative splic-
ing of several tumor suppressors and oncogenes in glio-
blastoma cells[72]. Furthermore, several studies reported
interactions and cooperation between these hnRNPs[77-79].
hnRNP A2 and hnRNP L have also been shown to ex-
ist as a complex and regulate the expression of glucose
transporter-1 by binding to mRNA 3’NTR[80,81].
In the HCV life cycle, hnRNPs are associated with
HCV genome RNA and regulate its replication. hnRNP
A1, which exhibits high homology with hnRNP A2/B1,
was shown to facilitate HCV replication via binding to
the HCV 5’ and 3’NTRs (Figure 1), and the replication
was significantly suppressed by the double knockdown
of hnRNP A1 and hnRNP A2[82]. hnRNP K and hnRNP
L are also NTR-binding proteins[83-85]. Furthermore, all
Affinity chromatography
Two-dimensional
electrophoresis
vs
Differential analysis
Mass spectrometric analysis
siRNA-based replicon assay
Total proteins extracted from HCV replicon cells
Proanthocyanidin-
binding proteins
Catechin-
binding proteins
Proteins having higher affinity to
proanthocyanidin than catechin
hnRNP A2/B1
hnRNP A/B
hnRNP K
hnRNP L
Figure 4 Identification strategy of candidate proteins involved in the
proanthocyanidin-mediated inhibition of hepatitis C virus subgenomic ex-
pression[13]. Total proteins were extracted from hepatitis C virus (HCV) replicon
cells and then proanthocyanidin-binding and catechin-binding proteins were
puried by afnity chromatography using sepharose beads coupled with pro-
anthocyanidin and catechin, respectively. Puried proteins were separated by
two-dimensional electrophoresis followed by detecting spots of proteins having
higher afnity to proanthocyanidin than catechin (arrows). Mass spectrometric
analysis and further screening by a siRNA-based replicon assay showed that
hnRNP A2/B1, A/B, K, and L are candidate proteins involved in the oligomeric
proanthocyanidin-mediated inhibition of HCV subgenomic expression. hnRNP:
Heterogeneous nuclear ribonucleoprotein.
Ishida Y
et al
. Oligomeric proanthocyanidin suppresses HCV subgenomic replication
876 December 27, 2014
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the hnRNPs we identied as the target protein candidates
of oligomeric proanthocyanidin were included in HCV
3’NTR-binding proteins[86]. Collectively, these findings
suggested that a complex composed of hnRNP A2/B1,
A/B, K, and L may serve in HCV genome replication
by binding to NTRs and oligomeric proanthocyanidin is
an inhibitor of the replication complex. This possibility
should be addressed in a further study.
CONCLUSION
Currently, a combination of pegylated recombinant in-
terferons and ribavirin is used as the standard therapy
for hepatitis C patients. Recently emerged DAAs are
expected to provide new promising treatment options in
hepatitis C patients. However, their high medical costs
may make difcult to disseminate worldwide. We demon-
strated that extracts of blueberry leaves suppressed HCV
subgenome replication in vitro, and their active ingredient
was oligomeric proanthocyanidin[13]. Investigations into
the underlying action mechanism suggested that proan-
thocyanidin may be an inhibitor of several hnRNPs such
as hnRNP A2/B1[13]. On the other hand, it currently re-
mains unknown whether the oligomeric form of proan-
thocyanidin, which is required for the inhibition of HCV
replication, can be efciently absorbed from the digestive
tract to maintain effective plasma concentrations in vivo.
However, further basic research on the action mechanism
of oligomeric proanthocyanidin against HCV replication
may open ways to develop novel anti-HCV drugs and
supplements for hepatitis C patients worldwide.
ACKNOWLEDGMENTS
We dedicate this work to Mr. Fumiaki Mieno (deceased,
March 19, 2013), who inspired our work in the protec-
tion and exploitation of intellectual property. We thank
Sachiko Tomiyama, Tokoyo Imai, Toshiro Morishita, and
Makoto Kodama (Miyazaki Prefectural Industrial Sup-
port Foundation) for coordinating our study.
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... Among polyphenols, the proanthocyanidins have a particular behavior, as described by Ishida, Takeshita, and Kataoka (2014). ...
... Indeed, a polymerization degree of 8-9, showed a remarkable dosedependent suppressive activity, probably due to the interaction of proanthocyanidin with hnRNP A2/B1, a key factor required for HCV subgenomic expression. Another hypothesis of inhibition is the binding of proanthocyanidin with the HCV IRES-mediated translation initiation complex, but other studies are needed to clarify and confirm this hypothesis (Ishida et al., 2014). ...
... Curcumin isolated by Curcuma longa L. is able to inhibit the entry of the HCV into the host cells; moreover, quercetin, naringenin, and PGU, some flavonoids abundant in berries, pomegranate and grapefruit, respectively, showed an inhibitory activity on a different stage of the HCV infectious process. The similarity between the three compounds suggests a structure-activity relationship able to modulate viral proteins and their associations with the host proteins (Ishida et al., 2014). ...
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Viral infections represent one of the main causes of disease worldwide, especially today due to the increase of migration, global travel, and urbanization. The several side effects of the conventional drugs and the growing phenomenon of resistance have led researchers to turn to the plant kingdom as a source of potential new antiviral drugs. The aim of this work is to summarize the updated evidence for antiviral activity of different plants and their isolated bioactive compounds, evaluating also the potential interactions, which can occur in cotreatment with conventional antiviral drugs. The plant complexes have proved to be usually more active than their most abundant isolated compounds by hypothesizing synergistic mechanisms. In addition to cellular and molecular investigations, molecular docking studies have proved essential in highlighting the interaction mechanisms of bioactive compounds with target molecules. However, the use of nonstandardized extracts, or too high concentrations in vitro, which do not reproduce their bioavailability in vivo, are often limiting factors. Moreover, the lack of studies concerning the safety profile of plant extracts and their isolated compounds, alone or in combination with conventional antiviral drugs, is the most worrying aspect. In light of this, further studies are needed to validate their possible therapeutic use.
... Human infection with HCV is currently recognized as the leading cause of chronic liver diseases such as hepatic steatosis, liver cirrhosis, and hepatocellular carcinoma (HCC), which demands liver transplantation (Ishida et al., 2014). Hepatitis C virus infection is a significant public health problem with approximately 200 million people around the world being infected with HCV (Tsantrizos, 2008;Ibrahim et al., 2013). ...
... Cynaropicrin having significant antitumor activity and it may be served as potential cancer chemopreventive lead drug for prevention or treatment of human cancers (Kang et al., 2007). Human infection with HCV is currently recognized as the leading cause of the severe complications such as HCC which demands liver transplantation (Ishida et al., 2014) since HCC is the major histological subtype of primary liver cancer (Hu et al., 2013). A total of ∼27% of individuals that develop liver cirrhosis and HCC worldwide arise in HCV-infected people (Ishida et al., 2014). ...
... Human infection with HCV is currently recognized as the leading cause of the severe complications such as HCC which demands liver transplantation (Ishida et al., 2014) since HCC is the major histological subtype of primary liver cancer (Hu et al., 2013). A total of ∼27% of individuals that develop liver cirrhosis and HCC worldwide arise in HCV-infected people (Ishida et al., 2014). It appears to be the major causative factor responsible for the recent doubling of HCC which was estimated to result in ∼10,000 deaths in the United States only in the year 2011 (Gonzalez et al., 2009;Ibrahim et al., 2013). ...
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The different pharmacologic properties of plants-containing cynaropicrin, especiallyartichokes, have been known for many centuries. More recently, cynaropicrin exhibiteda potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has alsoshown a wide range of other pharmacologic properties such as anti-hyperlipidemic,anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, andanti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatoryproperties (e.g., associated with the suppression of the key pro-inflammatory NF-κBpathway). These pharmacological effects are very supportive factors to its outstandingactivity agai nst HCV. Structurally, cynaropicrin might be considered as a potential drugcandidate, since it has no violations for the rule of five and its water-solubility could allowformulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that canbe easily synthesized and as the major constituent of the edible plant artichoke, whichhas a history of safe dietary use. In summary, cynaropicrin is a promising bioact ive naturalproduct that, with minor hit-to-lead optimization, might be developed a s a drug for HCV.
... Concerning HCV, Takeshika et al. [196,218] reported that purified PACs (PAC-B primarily) from blueberry leaves inhibited HCV RNA replication (EC 50 0.087 µg/mL, SI 212). This antiviral activity was evaluated using an HCV subgenomic expression system, while the adhesion/internalization stages of viral particles were not investigated. ...
... However, it was observed that blueberry leaf-derived PACs interacted with the heterogeneous nuclear ribonucleoprotein A2/B1 that is indispensable for HCV subgenome expression. Moreover, the anti-HCV activity was found dependent on the polymerization level of PACs, reaching the maximum efficacy with a polymerization degree between 8 and 9 [196,218]. Similarly, Li and coworkers [219] reported that PAC-B1 purified from a cinnamon bark extract inhibited HCV RNA synthesis in a concentration-dependent manner in Huh-7 cells, but it did not interfere with viral entry or receptor expression [219]. ...
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A-type proanthocyanidins (PAC-As) are plant-derived natural polyphenols that occur as oligomers or polymers of flavan-3-ol monomers, such as (+)-catechin and (−)-epicatechin, connected through an unusual double A linkage. PAC-As are present in leaves, seeds, flowers, bark, and fruits of many plants, and are thought to exert protective natural roles against microbial pathogens, insects, and herbivores. Consequently, when tested in isolation, PAC-As have shown several biological effects, through antioxidant, antibacterial, immunomodulatory, and antiviral activities. PAC-As have been observed in fact to inhibit replication of many different human viruses, and both enveloped and non-enveloped DNA and RNA viruses proved sensible to their inhibitory effect. Mechanistic studies revealed that PAC-As cause reduction of infectivity of viral particles they come in contact with, as a result of their propensity to interact with virion surface capsid proteins or envelope glycoproteins essential for viral attachment and entry. As viral infections and new virus outbreaks are a major public health concern, development of effective Broad-Spectrum Antiviral Agents (BSAAs) that can be rapidly deployable even against future emerging viruses is an urgent priority. This review summarizes the antiviral activities and mechanism of action of PAC-As, and their potential to be deployed as BSAAs against present and future viral infections.
... Hepatitis C virus belongs to the genus Hepacivirus, which infects about 170 million people in the world and causes high rates of chronic hepatitis (>75%), however oligomeric proanthocyanidin in blueberry leaves can inhibit RNA expression of the hepatitis C virus [78]. Diets containing blueberries markedly reversed the acrylamide-induced alterations in liver exerting strong antioxidant activities, significantly alleviating the DNA damage in liver cells [79]. ...
... Blueberry anthocyanins have protective effects on CCl4 induced hepatic fibrosis, which associated to decrease ROS producing sources and oxidative damage, as well as the influence of pro-inflammatory cytokines, inhibit the activity of hepatic stellate cells, downregulation TIMP1, PCNA, Col-III, α-SMA, and upregulation MMP-9 [120]. The action mechanism of oligomeric proanthocyanidin in blueberry leaves for resistant hepatitis C virus is an inhibitor of hnRNP A2/B1 [78]. The blueberry probiotics could antagonize the nonalcoholic fatty liver disease via the phosphor-Janus kinase-1/phosphor-signal transducer and activator of transcription 3 signaling pathway [121]. ...
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Functional ingredients in blueberry have the best health benefits. To obtain a better understanding of the health role of blueberry in chronic disease, we conducted systematic preventive strategies for functional ingredients in blueberry, based on comprehensive databases, especially PubMed, ISI Web of Science, and CNKI for the period 2008–2018. Blueberry is rich in flavonoids (mainly anthocyanidins), polyphenols (procyanidin), phenolic acids, pyruvic acid, chlorogenic acid, and others, which have anticancer, anti-obesity, prevent degenerative diseases, anti-inflammation, protective properties for vision and liver, prevent heart diseases, antidiabetes, improve brain function, protective lung properties, strong bones, enhance immunity, prevent cardiovascular diseases, and improve cognitive decline. The anthocyanins and polyphenols in blueberry are major functional ingredients for preventive chronic disease. These results support findings that blueberry may be one of the best functional fruits, and further reveals the mechanisms of anthocyanins and polyphenols in the health role of blueberry for chronic disease. This paper may be used as scientific evidence for developing functional foods, nutraceuticals, and novel drugs of blueberry for preventive chronic diseases.
... Some studies highlight the potential of the proanthocyanidin classes to induce activity against Hepatitis C virus ( Ishida et al., 2014), He- patitis B and D virus (Tsukuda et al., 2017), Herpes simplex virus type 1 (Gescher et al., 2011) and type 2 (Terlizzi et al., 2016), Respiratory syncytial virus ( Lee et al., 2017), Canine distemper virus ( Gallina et al., 2011), and Rotavirus ( Lipson et al., 2017). Reports have shown that oligomeric forms of proanthocyanidins inhibit adsorption and viral penetration (Gescher et al., 2011). ...
... Hepatitis C virus (HCV) infects 200 million people worldwide, and 75% of HCV cases progress into chronic infections. HCV infections are strongly associated with the progression of liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma (Takeshita et al. 2009, Gao et al. 2010, Lok et al. 2012, Ishida et al. 2014). ...
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Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. Current therapy for HCV infection includes the prolonged administration of a combination of ribavirin and PEGylated interferon-α, for over a decade. This regimen is expensive and often associated with a poor antiviral response and unwanted side effects. A highly effective combination treatment is likely required for the future management of HCV infections and entry inhibitors could play an important role. Currently, no entry inhibitor has been licensed for the prophylactic treatment of hepatitis C. Therefore, additional agents that combat HCV infection are urgently needed and must be developed. Many phytochemical constituents have been identified that display considerable inhibition of HCV at some stage of the life cycle. This review will summarise the current state of knowledge on natural products and their possible activities in the context of HCV infection.
... Herbal medicines are receiving much attention due to their lesser side effects, low cost extraction of therapeutic phytochemicals, lack of access to modern synthetic drugs, prototypic drug discovery, natural origin and safety [18]. A number of promising medicinal plants and purified natural products have been identified as potent anti-HCV agents [14,19,20]. ...
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Background: Without an effective vaccine, hepatitis C virus (HCV) remains a global threat, inflicting 170-300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma (HCC). Though various direct acting antivirals have been redeemed the hepatitis C treatment, a few restraints persist including possible side effects, viral resistance emergence, excessive cost which restricts its availability to a common person. Hypothesis: There is no preventive HCV vaccine available today so the discovery of potent antiviral natural flora and their bioactive constituents may help to develop preventive cures against HCV infection. Study design: In current study, we aim to clarify anti-HCV activity of methanol and acetone extracts along with the purified fractions of Pakistani local plant, Nymphaea alba L (N. alba) using Huh-7 cell line as transfection model. Synergistic study of purified fractions with interferon was performed using MDBK cell line (expressing interferon receptors) as transfection model. Materials and methods: Recent study by our research group has observed potent anti-HCV NS3 protease activity of methanol and acetone extracts of N. alba. Effect of N. alba extracts, its fractions precisely, the N1 and N8 fractions on HCV replication was demonstrated by analyzing viral gene expression using in vitro transfection model. Considering NS3 protease as a dynamic drug target, fourteen phytochemicals of N. alba were selected as ligands for interaction with NS3 protein using Molecular Operating Environment (MOE) software. Boceprevir, FDA approved NS3 protease inhibitor, was used as standard for comparative study in docking screening. Results: Herein we report 84% and 94% reduction of 3a genotype of HCV NS3/4A gene expression at mRNA level at non-toxic concentration. Specifically, two fractions 'N1' & 'N8' isolated from acetone extract suppressed HCV NS3 gene expression in transfected target cells with an EC50 value of 37 ± 0.03 μg/ml and 20 ± 0.02 μg/ml respectively. Similarly, viral genotype 1a replication is strongly suppressed in target cells by N. alba flower extracts and purified fractions. Moreover, combination of fractions with standard antiviral drug displayed synergistic effects for inhibition of HCV replication. Phytochemicals including Isoquercetin, Hyperoside, Quercetin, Reynoutrin, Apigenin and Isokaempferide displayed minimum binding energies as compared to standard protease inhibitor. Conclusion: N. alba and its purified phytochemicals with new scaffolds might significantly serve as valuable and alternative regimen against HCV either alone or in combination with other potential anti-HCV agents.
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PubMed ,Google Scholar ‫ﻳﺎﻓﺘﻪ‬ ‫ﻫﺎﻱ‬ ‫ﺍﺳﺖ‬ ‫ﭘﺮﺩﺍﺧﺘﻪ‬ ‫ﮔﺮﺍﻧﺒﻬﺎ‬ ‫ﻣﻴﻮﻩ‬ ‫ﺍﻳﻦ‬ ‫ﺧﻮﺍﺹ‬ ‫ﻣﻮﺭﺩ‬ ‫ﺩﺭ‬ ‫ﻭﺑﺮﺭﺳﻲ‬ ‫ﺑﺤﺚ‬ ‫ﻭﺑﻪ‬ ‫ﺷﺪﻩ‬ ‫ﺍﺳﺘﺨﺮﺍﺝ‬ ‫ﺟﺪﻳﺪ‬ ‫ﻋﻠﻤﻲ‬. ‫ﻫﺎ‬ ‫ﻳﺎﻓﺘﻪ‬ : ‫ﺑﺎﺭﺯ‬ ‫ﺧﺎﺻﻴﺖ‬ ‫ﻳﻚ‬ ‫ﺩﺍﺭﺍﻱ‬ ‫ﻭﺭﻳﺸﻪ‬ ‫ﻭﺑﺮگ‬ ‫ﺳﺎﻗﻪ‬ ‫ﻭ‬ ‫ﻭﻣﻴﻮﻩ‬ ‫ﮔﻞ‬ ‫ﺍﺯ‬ ‫ﺁﻥ‬ ‫ﻣﺨﺘﻠﻒ‬ ‫ﺍﺟﺰﺍء‬ ‫ﻛﻪ‬ ‫ﺍﺳﺖ‬ ‫ﮔﻴﺎﻫﻲ‬ ‫ﺍﻳﺮﺍﻧﻲ‬ ‫ﻃﺐ‬ ‫ﺩﺭ‬ ‫ﺍﻧﺎﺭ‬ ‫ﻣﻲ‬ ‫ﺍﻧـﻮﺍﻉ‬ ‫ﺗﻤﺎﻡ‬ ‫ﺩﺭ‬ ‫ﻛﻪ‬ ‫ﺧﺎﺻﻴﺖ‬ ‫ﺍﻳﻦ‬ ‫ﺑﺎﺷﻨﺪ‬ ‫ﻭﺷﻴﺮﻳﻦ‬ ‫ﺗﺮﺵ‬ ‫ﺍﺯ‬ ‫ﺍﻧﺎﺭ‬ ‫ﺗﻘﻮﻳﺖ‬ ‫ﻋﺚ‬ ‫ﺑﺎ‬ ‫ﺑﺎﺷﺪ‬ ‫ﺩﺍﺷﺘﻪ‬ ‫ﻗﺒﺾ‬ ‫ﻛﻪ‬ ‫ﺍﻱ‬ ‫ﻣﺎﺩﻩ‬ ‫ﻫﺮ‬ ‫ﺍﻳﺮﺍﻧﻲ‬ ‫ﻃﺐ‬ ‫ﺑﺮﺍﺳﺎﺱ‬ ‫ﺍﺳﺖ‬ ‫ﻗﺒﺾ‬ ‫ﺧﺎﺻﻴﺖ‬ ‫ﺩﺍﺭﺩ‬ ‫ﻭﺟﻮﺩ‬ ‫ﻭﻣﻠﺲ‬ ‫ﻣﻲ‬ ‫ﻭﺍﺭﺩ‬ ‫ﻛـﻪ‬ ‫ﻋﻀـﻮ‬ ‫ﻫﺮ‬ ‫ﺩﺭ‬ ‫ﺷﻮﺩﻭ‬ ‫ﺁﻥ‬ ‫ﺑﻪ‬ ‫ﺳﻤﻮﻡ‬ ‫ﻭﺭﻭﺩ‬ ‫ﻣﺎﻧﻊ‬ ‫ﻋﻀﻮ‬ ‫ﻋﻤﻠﻜﺮﺩﺁﻥ‬ ‫ﺗﻘﻮﻳﺖ‬ ‫ﺑﺮ‬ ‫ﺷﻮﺩﻋﻼﻭﻩ‬ ‫ﻣﻲ‬ ‫ﺷﻮﺩ‬. ‫ﺯﺧﻢ،ﻣﻤ‬ ‫ﺑﻬﺒـﻮﺩ‬ ‫ﺧـﻮﻧﺮﻳﺰﻱ،‬ ‫ﺍﺯ‬ ‫،ﻛﺒـﺪ،ﻣﻤﺎﻧﻌﺖ‬ ‫ﻣﻌـﺪﻩ‬ ‫ﺗﻘﻮﻳـﺖ‬ ‫ﺩﺭ‬ ‫ﺍﻧﺎﺭ‬ ‫ﺍﻳﻦ‬ ‫ﺑﻨﺎﺑﺮ‬ ‫ﺍﻳﺠـﺎﺩ‬ ‫ﺍﺯ‬ ‫ﺎﻧﻌـﺖ‬ ‫ﺳﺮﺩ‬ ‫ﺑﺎ‬ ‫ﻣﺸﺎﺭﻙ‬ ‫ﺭﺩﻫﺎﻱ‬ ، ‫ﺁﻟﺮ‬ ‫ﺿﺪ‬ ‫ﺣﻠﻖ،ﺍﺛﺮﺍﺕ‬ ‫ﭘﺸﺖ‬ ‫ﺗﺮﺷﺤﺎﺕ‬ ‫ﻛﺮﺩﻥ‬ ‫ﻭﺑﻴﻨﻲ،ﺑﺮﻃﺮﻑ‬ ‫ﻭﺣﻠﻖ‬ ‫ﮔﻮﺵ‬ ‫ﺑﻴﻤﺎﺭﻳﻬﺎﻱ‬ ‫ﺑﻬﺒﻮﺩ‬ ‫ژ‬ ‫ﻋﺮﻭﻗﻲ،ﺿﺪ‬ ‫ﻗﻠﺒﻲ‬ ‫ﺑﻴﻤﺎﺭﻳﻬﺎﻱ‬ ‫ﻭﺿﺪ‬ ‫ﻣﻴﻜﺮﻭﺑﻲ‬ ‫ﻭﺿﺪ‬ ‫ﻱ‬ ‫ﻣﻮﺛﺮ‬ ‫ﭘﻮﺳﺘﻲ‬ ‫ﻣﺸﻜﻼﺕ‬ ‫ﺑﺮﺧﻲ‬ ‫ﺩﻳﺎﺑﺖ،ﺩﺭﻣﺎﻥ‬ ‫،ﻛﻨﺘﺮﻝ‬ ‫ﺍﻟﺘﻬﺎﺑﻲ‬ ‫ﻭﺿﺪ‬ ‫ﺳﺮﻃﺎﻧﻲ‬ ‫ﻣﻲ‬ ‫ﺑﺎﺷﺪ‬. ‫ﻧﺘﻴﺠﻪ‬ ‫ﮔﻴﺮﻱ‬ : ‫ﻭﺩﺳﺘﺎﻭﺭﺩﻫﺎ‬ ‫ﻗﺪﻳﻢ‬ ‫ﺳﺎﻟﻪ‬ ‫ﺻﺪ‬ ‫ﭼﻨﺪ‬ ‫ﺗﺠﺮﺑﻴﺎﺕ‬ ‫ﺑﻪ‬ ‫ﺗﻮﺟﻪ‬ ‫ﺑﺎ‬ ‫ﺍﻧﺎﺭ‬ ‫ﮔﻴﺎﻩ‬ ‫ﺍﻣﺮﻭﺯ‬ ‫ﺩﺍﻧﺶ‬ ‫ﻱ‬ ‫ﻣﻲ‬ ‫ﺑـﻪ‬ ‫ﻣﻜﻤـﻞ‬ ‫ﺻﻮﺭﺕ‬ ‫ﺑﻪ‬ ‫ﻳﺎ‬ ‫ﺗﻨﻬﺎﻳﻲ‬ ‫ﺑﻪ‬ ‫ﺑﻴﻤﺎﺭﻳﻬﺎ‬ ‫ﺍﺯ‬ ‫ﺑﺴﻴﺎﺭﻱ‬ ‫ﺩﺭﻣﺎﻥ‬ ‫ﺩﺭ‬ ‫ﺗﻮﺍﻧﺪ‬ ‫ﺷﻮﺩ‬ ‫ﮔﺮﻓﺘﻪ‬ ‫ﻛﺎﺭ‬. ‫ﺗﻮﺻﻴﻪ‬ ‫ﺁﻧﻬﺎ‬ ‫ﺗﺠﺮﺑﻲ‬ ‫ﺑﺮﺭﺳﻲ‬ ‫ﻣﻲ‬ ‫ﺷﻮﺩ‬ ‫ﻛﻠﻴﺪﻭﺍژﻩ‬ ‫ﻫﺎ‬ : ‫ﻗﺒﺾ‬ ‫ﺍﻣﺮﻭﺯ،ﺧﺎﺻﻴﺖ‬ ‫ﺍﻳﺮﺍﻥ،ﻃﺐ‬ ‫ﺳﻨﺘﻲ‬ ‫ﺍﻧﺎﺭ،ﻃﺐ‬. ‫ﻣﻘﺪﻣﻪ‬ : ‫ﺷﻨﺎﺳـﻲ‬ ‫ﮔﻴـﺎﻩ‬ ‫ﻧـﺎﻡ‬ ‫ﺑـﺎ‬ ‫ﺍﻱ‬ ‫ﻣﻴـﻮﻩ‬ ‫‪‬ﺎﻥ،‬ ‫ﻣ‬ ‫ﺭ‬ ‫ﻋﺮﺑﻲ‬ ‫ﺑﻪ‬ ‫ﺍﻧﺎﺭ‬ Punica granatum ‫ﺗﻴﺮﻩ‬ ‫ﺍﺯ‬ punicaceae ‫ﻣﻲ‬ ‫ﺑﺎﺷﺪ‬. ‫ﺑﺎﺳـﺘﺎﻥ‬ ‫ﻻﺗـﻴﻦ‬ ‫ﺯﺑﺎﻥ‬ ‫ﺩﺭ‬ pumum ‫ﻭ‬ ‫ـﻴﺐ‬ ‫ﺳـ‬ ‫ـﺎﻱ‬ ‫ﻣﻌﻨـ‬ ‫ـﻪ‬ ‫ﺑـ‬ granatum ‫ـﺘﻪ‬ ‫ﻫﺴـ‬ ‫ـﺮ‬ ‫ﭘـ‬ ‫ـﻲ‬ ‫ﻣﻌﻨـ‬ ‫ـﻪ‬ ‫ﺑـ‬ ‫ﻣﻲ‬ ‫ﺑﺎﺷﺪ،‬ ‫ﺑﻨﺎﺑﺮﺍﻳﻦ‬ Punica granatum ‫ﻫﺴﺘﻪ‬ ‫ﭘﺮ‬ ‫ﺳﻴﺐ‬ ‫ﻳﻌﻨﻲ‬. ‫ﺍﺳـﺖ‬ ‫ﺍﻳﺮﺍﻥ‬ ‫ﺗﻤﺪﻥ‬ ‫ﺍﻧﺎﺭ‬ ‫ﺧﻮﺍﺳﺘﮕﺎﻩ‬. ‫ﺍﺯ‬ ‫ﺗـﺪﺭﻳﺞ‬ ‫ﺑـﻪ‬ ‫ﺁﻥ‬ ‫ﺍﺯ‬ ‫ﺑﻌـﺪ‬ ‫ﻳﺎﻓﺖ‬ ‫ﻫﻨﺪﮔﺴﺘﺮﺵ‬ ‫ﺷﻤﺎﻝ‬ ‫ﺗﺎ‬ ‫ﻣﺪﻳﺘﺮﺍﻧﻪ‬. ‫ﻗﺮﻥ‬ ‫ﺍﻭﺍﺧﺮ‬ ‫ﺩﺭ‬ ‫ﻣﻴﻮﻩ‬ ‫ﺍﻳﻦ‬ 19 ‫ﺷﺪ‬ ‫ﺁﻣﺮﻳﻜﺎ‬ ‫ﻭﺍﺭﺩ‬ ‫ﻭ‬ ‫ﻛﺸﺖ‬ ‫ﻣﺨﺘﻠﻒ‬ ‫ﻛﺸﻮﺭﻫﺎﻱ‬ ‫ﺩﺭ‬ ‫ﺍﻣﺮﻭﺯﻩ‬ ‫ﻣﻲ‬ ‫ﺷﻮﺩ‬. ‫ﺗ‬ ‫ﺑﺰﺭﮔﺘﺮﻳﻦ‬ ‫ﺍﻳﺮﺍﻥ‬ ‫ﻛﺸـﻮﺭ‬ ‫ﺩﻭﻣـﻴﻦ‬ ‫ﻭﻫﻨﺪﻭﺳـﺘﺎﻥ‬ ‫ﺩﻧﻴﺎ‬ ‫ﺍﻧﺎﺭ‬ ‫ﻮﻟﻴﺪﻛﻨﻨﺪﻩ‬ ‫ﺍﺳﺖ‬ .) 1 (‫ﺗـﺎ‬ ‫ﺣﺪﺍﻛﺜﺮ‬ ‫ﺁﻥ‬ ‫ﺍﺭﺗﻔﺎﻉ‬ ‫ﻛﻪ‬ ‫ﺍﺳﺖ‬ ‫ﻛﻮﭼﻜﻲ‬ ‫ﺩﺭﺧﺖ‬ ‫ﺍﻧﺎﺭ‬ 6 ‫ﻣﺘﺮ‬ ‫ﻣﻲ‬ ‫ﻣﻴﺮﻭﻳﺪ‬ ‫ﮔﺮﻣﺴﻴﺮﻱ‬ ‫ﻧﻴﻤﻪ‬ ‫ﻣﻨﺎﻃﻖ‬ ‫ﺩﺭ‬ ‫ﻭ‬ ‫ﺭﺳﺪ‬. ‫ﮔـﻞ‬ ‫ﻫـﺎﻱ‬ ‫ﺍﻧـﺎﺭ‬ ‫ﺑﻮ‬ ‫ﺑﻲ‬ ‫ﻭﻟﻲ‬ ‫ﺍﻧﺎﺭﻱ‬ ‫ﻗﺮﻣﺰ‬ ‫ﺭﻧﮓ‬ ‫ﺑﻪ‬ ‫ﺩﺭﺷﺖ،‬ ‫ﻣﻲ‬ ‫ﺑﺎﺷﺪ‬. ‫ﮔﻞ‬ ‫ﻫﺎﻱ‬ ‫ﺑﺮ‬ ‫ﺍﻧﺎﺭ‬ ‫ﺍﻧﺪ‬ ‫ﻧﻮﻉ‬ ‫ﺩﻭ‬ : ‫ﮔﻞ‬ ‫ﺍﻭﻝ‬ ‫ﺩﺳﺘﻪ‬ ‫ﻫـﺎﻱ‬ ‫ﺛﻤـﺮﻱ‬ ‫ﻳـﺎ‬ ‫ﺑـﺎﺭﺁﻭﺭ‬ (fruitful) ‫ﻛـﻪ‬ ‫ﺁﻥ‬ ‫ﺩﺭ‬ ‫ـﻪ‬ ‫ﻛـ‬ ‫ـﺘﻨﺪ‬ ‫ﻫﺴـ‬ ‫ـﺪ‬ ‫ﺑﻠﻨـ‬ ‫ـﺮﭼﻢ‬ ‫ﭘـ‬ ‫ﻭ‬ ‫ـﻪ‬ ‫ﺧﺎﻣـ‬ ‫ﺩﺍﺭﺍﻱ‬ ‫ﻭ‬ ‫ـﻮﺩﻩ‬ ‫ﺑـ‬ ‫ﺑﺰﺭﮔﺘـﺮ‬ ‫ﺑﺴﺎﻙ‬ ‫ﻫﺎ‬ ‫ﻛﻼﻟﻪ‬ ‫ﻭ‬ ‫ﻫﺎ‬ ‫ﻫﺴﺘﻨﺪ‬ ‫ﻗﺪ‬ ‫ﻫﻢ‬ ً ‫ﺗﻘﺮﻳﺒﺎ‬. ‫ﮔـﻞ‬ ‫ﺍﻳـﻦ‬ ‫ﻫـﺎ‬ ‫ﻭ‬ ‫ﻛﺸـﻴﺪﻩ‬ ‫ـﻞ‬ ‫ﮔـ‬ ‫ـﺮﺩﻥ‬ ‫ﮔـ‬ ‫ﺩﺭ‬ ‫ـﺎﻥ‬ ‫ﻗﻄﺮﺷـ‬ ‫ﺍﺯ‬ ‫ـﺘﺮ‬ ‫ﺑﻴﺸـ‬ ‫ـﺎﻝ‬ ‫ﺍﺗﺼـ‬ ‫ـﻞ‬ ‫ﻣﺤـ‬ ‫ﺩﺭ‬ ‫ـﺎﻥ‬ ‫ﻗﻄﺮﺷـ‬ ‫ﻣﻲ‬ ‫ﺑﺎﺷﺪ‬. ‫ﮔﻞ‬ ‫ﺩﻭﻡ‬ ‫ﺩﺳﺘﻪ‬ ‫ﻫﺎﻱ‬ ‫ﻭ‬ ‫ﻧﺎﺯﺍ‬ ‫ﻋﻠﻔﻲ‬ ‫ﻳﺎ‬ (barren) ‫ﻛـﻪ‬ ‫ﻫﺴﺘﻨﺪ‬ ‫ﺁﻧﻬـﺎ‬ ‫ﺩﺭ‬ ‫ﻭ‬ ‫ﺑـﻮﺩﻩ‬ ‫ﻛﻮﺗـﺎﻩ‬ ‫ﭘـﺮﭼﻢ‬ ‫ﻭ‬ ‫ﺧﺎﻣـﻪ‬ ‫ﺑﺎ‬ ‫ﺗﺮ‬ ‫ﻛﻮﭼﻚ‬ ‫ﺁﻧﻬﺎ‬ ‫ﺍﻧﺪﺍﺯﻩ‬ ‫ﻛﻼﻟﻪ‬ ‫ﻫﺎ‬ ‫ﺑﺴﺎﻙ‬ ‫ﺯﻳﺮ‬ ‫ﺩﺭ‬ ‫ﻭ‬ ‫ﺗﺮ‬ ‫ﻛﻮﺗﺎﻩ‬ ‫ﻫﺎ‬ ‫ﺩﺍﺭﻧﺪ‬ ‫ﻗﺮﺍﺭ‬. ‫ﮔـﻞ‬ ‫ﺍﻳﻦ‬ ‫ﻫـﺎ‬ ‫ﻛـﻪ‬ ً ‫ﺑﻌـﺪﺍ‬ ‫ﺍﺳـﺖ‬ ‫ﮔﺮﺩﻥ‬ ‫ﺩﺭ‬ ‫ﻗﻄﺮﺷﺎﻥ‬ ‫ﺍﺯ‬ ‫ﻛﻤﺘﺮ‬ ‫ﺍﺗﺼﺎﻝ‬ ‫ﻣﺤﻞ‬ ‫ﺩﺭ‬ ‫ﻗﻄﺮﺷﺎﻥ‬ ‫ﺗﺎﺭ‬ ‫ﻳ‬ ‫ﺦ‬ ‫ﺩﺭ‬ ‫ﻳ‬ ‫ﺎﻓﺖ‬ : ‫ﺍﺭﺩﻳﺒﻬﺸﺖ‬ 95 ‫ﭘﺬﻳﺮﺵ‬ ‫ﺗﺎﺭﻳﺦ‬ : ‫ﺑﻬﻤﻦ‬ 95
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A series of novel bicyclic proline P-2 scaffold based tetrapeptide inhibitors were designed and prepared. Given their relatively small size, these compounds exhibited exceptional binding affinities and good cellular potencies for HCV protease. One of the best analogues, tricyclic based P-2 scaffold 12, had an affinity for HCV with a Ki of 37 nM and cell activity IC50 of 200 nM.
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Background An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Methods We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Findings This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85—94) patients in the treatment-naive cohort, 168 (82%, 77—87) in the non-responder cohort, and 192 (82%, 77—87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). Interpretation Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis.
Article
Background: Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. Methods: In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. Findings: 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment). Interpretation: Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin. Funding: Janssen Infectious Diseases-Diagnostics.
Article
Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.