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Page 6 of 14 Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25

interfere with HCV entry during post binding process [48-53] . SRB1 proteins, related to lipid metabolism,
also affect HCV entry to host cells . Serum amyloid A, an acute phase protein and produced by liver,
[54]
inhibits HCV entry [55-57] . Similarly, ITX5061, a small molecule, also blocks uptake of HCV and functions
synergistically with DAAs, thus giving a promise for future use. CLDNs and OCLNs form complex with CD81
and contribute to efficient HCV internalizations. Since CLDN1 is highly expressed in hepatocytes, it may be
a potential target for antiviral agents. Antibodies vs. CLDN1 show inhibitory effect on HCV infection [58-60] .
OCLN is also a main entry factor for HCV. Recently, it has been found that mi R-122 can decrease HCV
entry by inhibiting OCLN. The EGFR and EphA2, the receptor tyrosine kinases (RTKs), act as cofactors for
HCV entry . These are expressed in liver and inhibited by anticancer drugs like Erlotinib and Desatinib.
[61]
These drugs impair HCV cell-entry. RTKs interfere with CD81-CLDN1 complex association and block cell
to cell transmission of HCV . However, their efficiency needs further authentication. After interaction with
[61]
various receptors, HCV particles are internalized through clatherin-mediated endocytosis . CD81-CLDN1
[62]
complex facilitates virus entry and fusion simultaneously . The compound chloropromazine interferes with
[58]
clatherin, thus impairing HCV endocytosis . Arbidol, used as an anti-influenza drug, impairs clatherin
[63]
mediated endocytosis of HCV . The fusion of virus membrane to host cell is followed by viral replication
[64]
inside the cell. The indole derivative arbidol also inhibits HCV membrane fusion . Silymarin is a mixture
[65]
[66]
of several flavonolignans and flavonoid taxifolines and inhibits fusion as done by arbidol . Other fusion
inhibitors include feroquine and aclorocquin, etc.
HCV replication as target
The HCV replication cycle presents another important target for antiviral therapy. The successful use of
protease inhibitors for the treatment of HIV infections prompted researchers to focus on the HCV associated
enzymes including NS3-4A protease and NS5B polymerase, etc. [67,68] . The HCV RdRp also became an
attractive drug target. Finally, inhibitors targeting NS5A have also been developed. Simultaneous with viral
proteins, several host cellular components were also used as targets while developing drugs against them.

NS3 is a component of HCV encoded polyprotein which together with NS4A, constitutes the protease
NS3-4A. Its carboxy-terminal region shows RNA helicase and NTPase activity . Both these proteases
[69]
are essential for HCV replication and have been pursued as drug targets. Since NS3-4A binds with its
substrate by weak interactions, this restricts the development of drugs targeting NS3-4A. However, later
studies could be successful in developing certain DAAs targeting NS3-4A . These drugs were put under
[70]
three different categories on the ground of their properties and action . The DAAs in category I include
[71]
linear peptidomimetics that bind proteases enzymes through covalent bonds. For example, telaprevir and
boceprevir, the drugs of class I bind to the active-site Ser (Serine) forming a covalent enzyme - inhibitor
adduct. This not only shows antiviral activity but also uses strong forces to bind the target site. DAAs under
category II and III are NS3-4A specific drugs. These are linear peptidomimetics or macrocyclic inhibitors
and do not bind with their target by covalent bonds. It has been reported that these drugs do not target all
HCV genotypes. These NS3-4A inhibitors are two macrocycles MK-5172 and ACH-2684 .
[72]
[73]
The NS5A replicase is the most enigmatic HCV protein. On the basis of molecular masses, their predominant
forms are p56 and p58, respectively . The phosphorylation in NS5A replicase is reported to be mediated
[74]
by different kinases [75,76] . It has several sites identified as targets in the central and c-terminal part of NS5A
and LCS1 region. The RdRp-NS5B is another enzyme regulating viral RNA synthesis. Several studies have
demonstrated the candidate NS5B inhibitors which are nucleoside and nucleotide inhibitors (NIs) in nature
and bind at active site of the enzyme. The non-nucleoside inhibitors (NNIs) bind at allosteric sites to bring
conformational changes and inhibit polymerase activity [67,68,71] . These NIs have been reported to be effective
against several HCV genotypes.

HCV replication is a complex process involving many other viral proteins simultaneous with NS3-4A, NS5A
and NS5B. These proteins have been pursued as drug targets. Moreover, there are some non-enzymatic