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Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25 Page 5 of 14

than IFN, but there are still a few cases of adverse reactions and reactivation of HBV during DAAs anti-HCV
treatment .
[31]

Cyclosporine and miravirsen
Cyclophilins including cyclophilins A, B, and C are involved in HCV replication. An immunosuppressive
compound cyclosporine A is involved in the inhibition of HCV RNA replication by interfering with
cyclophilins A functions. Alisporivir (Debio-025) which is a derivative of cyclosporine A acts as antiviral
agent against many HCV genotypes. The antiviral effect of cyclophilin inhibitors is increased when used in
combination with PegIFN-α. Thus, in addition to many other benefits, these agents may be used as effective
antiviral agents [33,34] . Miravirsen is another drug that targets miRNA-122. It inhibits several HCV genotypes
in vitro. Its effect lasts long simultaneous with non-appearance of resistant mutations.

Other antiviral agents
In addition to antiviral agents described above, vitamin B12 was also reported to act as an inhibitor of HCV
replication. The use of vitamin B12 with SOC drugs raised the SVR rate to the level higher than the rate
noted in patients treated with SOC alone . Recently, it has been observed that vitamin D also acts against
[35]
HCV in vitro. The SVR rate of patients infected with HCV genotype-1 or 2/3 is improved once vitamin D
is added to PegIFN-α and ribavirin therapy [36,37] . A comparison of study using PegIFN-α and RBV with
supplement of L-carnitine group vs. the PegIFN-α plus RBV group has shown an increase in SVR rate .
[38]
This substantiates that L-carnitine may be useful for the treatment of HCV infection.

MECHANISM OF DRUG-ACTION
Targets of drugs
The basic aim of designing the drugs against HCV infection is to develop agents that can check the entry of
virus into cells, blocks its replication and disrupts the viral assembly inside the cell. As such, drugs do not
kill the virus or its components but prevent their formation and reproduction. In case of HCV infection,
attempts were made to develop drugs that can check viral entry and replication process. Since the discovery
of HCV, a number of experimental studies were conducted which reported detailed analysis of HCV life
cycle and its interaction with human host. These studies revealed several targets for therapeutic intervention
in HCV infection. Recent improvements in the SOC therapy have raised the hope that HCV infection can be
managed with adequate medical intervention. However, the current treatment is not effective for all seven
genotypes. The basic aim for HCV therapy is to achieve high SVR using traditional drugs in combination
with direct acting antivirals (DAAs), without any chance of escape mutations.

HCV entry as target
The drugs inhibiting HCV entry into cells target receptors and enzymes helping in viral entry process.
These entry inhibitors have prophylactic properties and show synergistic effect when combined with other
agents . Circulating virions bind with glycosaminoglycans (GAGs) and LDLA . The lectin cyanovirin-N
[40]
[39]
(CV-N) impairs viral binding by its interaction with E1/E2 HCV proteins to check entry . Similarly, L-ficolin
[41]
proteins can neutralize HCV particles through their binding to E1/E2 proteins . Epigallocatechins gallate
[42]
(ECGC), a natural polyphenol compound and abundant in green tea extract regulate lipid metabolism impairs
HCV binding to host cell by interfering with HCV E1/E2 function and also block cell-to-cell transmission
in vitro [43-45] . This is the reason that green tea is considered as an effector against HCV infection. Lactoferin,
present in milk, also blocks HCV attachment . Like E1/E2, the P7 protein also inhibits HCV entry by
[46]
[47]
directly effecting virus binding to cell surface and interfering with host-virus interaction .
After attachment of virus with cell surface, its entry requires different host factors like CD81, SRB1, CLDN1
and OCCDN1, jfRI, EGFR, EphA2 and NPC1-L1, etc. CD81 interacts with HCV E2 helping HCV infection.
Specific NTCD81 monoclonal antibodies like JS-81 or KO4 counteract HCV E2-CD81 interactions and