Potential targets for antiviraldevelopment against HEVFollowing stages of HEV life cycle arepotential targets for the development of specific antivirals.

(a) Virus entry intothe host cell: Specific receptor for HEV entry into the host cells is unknown. However,it has been demonstrated that heparin sulfate proteoglycans (HSPGs) may serveas an attachment receptor to facilitate HEV entry into the host (63). The HEVcapsid protein (ORF2) also interacts with heat shock protein 90 (HSP90) andglucose-regulated protein 78 (Grp78). Grp78 or HSP90 may be involved in theintracellular transport of the virus (64, 65).

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Grp78 has also been shown to interact with the envelope protein of the Japaneseencephalitis virus (JEV), facilitating its entry into the host cells (66). It remains to be tested whether GRP78 andORF2 interaction mediates HEV entry. Inhibitiors of receptor binding orintracellular transport of the virus are supposed to block viral life cycle ata very early stage.(b) Capping of theviral genome: Among the non-structural proteins encoded by the HEV ORF1,methyltransferase is responsible for capping of the viral genome (67). Additionof a 7-methylguanosine cap at the 5′- terminus of the viralgenome confers stability and protects the viral RNA from the host innate immuneeffectors (68). Uncapped HEV RNA is inefficient in replication (69). Moreover,in contrast to the host methyltransferases, where guanyltransferase donates aGMP moiety to the RNA, followed by cap methylation byguanine-7-methyltransferase activity; HEV methyltransferase follows a reverseorder, thereby restricting its activity to the viral RNA (67).

Therefore,inhibition of HEV methyltransferase activity appears to be a potent antiviralstrategy. It is noteworthy that Neplanocin A and3-deaza-adenosine, the two known inhibitors of influenza virusmethyltransferases, interfere with virus replication (70). Neplanocin Ais also a potent inhibitor of vaccinia virus replication (71).  Inhibitors against Dengue virusmethyltransferases have also been screened (72).

(c) Replication of theviral genome: (i)   Direct actinginhibitors of HEV RNA dependent RNA polymerase (RdRp) function: RdRp is the mostimportant factor in the life cycle of all RNA viruses and therefore, RdRpinhibitors are supposed to be potent antivirals. One such antiviral against HCVis Sofosbuvir, which acts by inhibiting the activity of HCV RdRp (73). Dao etal indicated the effectiveness of Sofosbuvir in inhibiting HEV replication. However, subsequent studies failed to observe itspotent inhibitory effect (52-54). Nevertheless, optimization of Sofosbuvirstructure that improves its inhibitory effect on HEV RdRp appears to be anattractive area of investigation. Knowledge of HEV RdRp structure mightexpedite the above study.

Apart from Sofosbuvir like molecules, new chemicalentities should be explored to identify potent inhibitors of HEV RdRp activity.(ii) Other inhibitorsof HEV RdRp function: The interaction between host eEF1?1 and viral RdRp hasbeen shown to be important for optimal RdRp activity (74). Our recent study hasidentified additional RdRp interacting host factors, which are crucial forvirus replication (75). Inhibitors against these interactions are supposed toblock viral replication. A combination of direct and indirect inhibitors ofRdRp function might prove to be an apt antiviral strategy against HEV.(iii) Inhibitors of helicase function: HEV helicase is anucleoside triphosphatase with the ability to unwind RNA duplexes in the 5 to 3′ direction, thusplaying a role in HEV replication (76). Due to the common properties sharedbetween the helicases encoded by viruses and their host, designing inhibitorsagainst helicases is challenging. Nevertheless, potent inhibitors of helicaseencoded by herpes simplex virus (HSV), severe acute respiratory syndromecoronavirus (SARS CoV), HCV, dengue virus, JEV, west nile virus (WNV), andhuman papillomavirus (HPV) have been reported (77).

The new series of thiazolylphenyl-containing HSV helicase-primaseinhibitors are active in animal models and offer a new option for treatingacyclovir resistant latent HSV infections (78). (d) Release of theprogeny virions: Release of the progeny virions from infected cells leadto the infection of neighboring uninfected cells, thus amplifying the unwantedconsequences. Antivirals that prevent the release of the progeny virus willprevent further infection, thereby minimizing progression of the disease.  Release of the newly assembled virus from aninfected cell is a complicated process involving multiple protein-proteininteractions between the virus and host factors (79). A thorough understandingof such interactions helps in decoding the mechanism underlying virus release.

An inhibitor of HIV release has been identified, which acts by blocking theinteraction between the viral gag and host TSG101 (Tumor susceptibility gene101) proteins (80). Interaction between HEV ORF3 and host TSG101 protein isalso known to mediate the release of genotype-3 HEV (81, 82). An inhibitoragainst the above interaction may prove to be a potent antiviral against HEV.Apart from that, detailed investigation of HEV release mechanism shouldidentify additional targets for antiviral development. Conclusion:Theadvantages of using antivirals particularly to cut off the disease in aninfected person and providing treatment to poor responders to vaccine such asimmune-compromised patients warrants the need for development of specific drugsagainst HEV.  As summarized in Table 1, anumber of promising antiviral candidates have been identified through theefforts of several researchers, which should be further characterized toidentify one or more potent inhibitor(s) of HEV.

A combinatorial therapytargeting crucial virus-encoded factors at different stages of viral life cycleas well as inhibition of virus-host interactions should be a potent antiviralstrategy against HEV. The recent finding of HEV inhibitory activity of zincalso appears to be an attractive area for further investigation. Zinc directlyinhibits HEV RdRp activity in vitroand displays moderate cooperativity with ribavirin in inhibiting viralreplication in mammalian cell culture models of HEV infection. Therefore, evena moderate increase in the level of bioavailable zinc may significantly improvethe therapeutic benefits when combined with ribavirin therapy. In summary,recent studies have identified multiple leads, which should be pursued furtherto develop a potent antiviral against HEV.