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lphated polymer based inhibitors, which interact directly with viral envelope glycoproteins and stop viral Decitabine attachment, are now becoming tested in Phase II or III clinical trials . Helicase primase complex is essential for the unwinding of dsDNA as well as the generation of primers for DNA synthesis . Aminothiazolylphenyl compounds and thiazolyl sulphonamide compound , that stop the propagation of helicase primase catalytic cycle and inhibit its ATPase activity, respectively, display potent anti HSV effects in mice . Viral DNA polymerase is essential for DNA replication . 4 Hydroxyquinoline 3 carboxamides , that compete with incoming nucleotides and dislodge the template from the active website, display anti herpes virus activities in preclinical animal studies .
In principle, all the replicationessential viral proteins may be considered as potential targets for chemotherapy. This has raised the question. Is UL12 a possible candidate for anti herpes virus therapy? Although UL12 mutants are in a position to synthesize near wild sort levels of viral DNA, the yields of mutant Decitabine virus are reduced by 100 to 1000 fold . UL12 mutants display the failure of DNA containing capsids to migrate into the cytoplasm as well as the additional complex structure of replicative intermediates with an increased frequency of branches . Additionally, antisense phosphorothioate oligonucleotides, targeting an internal commence codon of HSV 1 UL12 mRNA, inhibit HSV 1 replication in Vero cells . In addition, emodin, that inhibited UL12 activity in vitro, displayed the reduction of HSV 1 yields in Vero cells in this study.
These findings indicated that UL12, that is conserved in all Doxorubicin species of Herpesviridae, may be considered as the target for the anti herpes virus therapy. Emodin, the active principle of herbal medicine derived from genera Rheum and Polygonum, has demonstrated antiviral effects to some enveloped viruses, for instance hepatitis B virus, HSV, human cytomegalovirus and serious acute respiratory syndrome coronavirus, and non enveloped viruses, for instance poliovirus . A number of studies have revealed that the antiviral activity of emodin is through casein kinase 2 inhibition, that is exploited by viruses for the phosphorylation of proteins which can be essential for viral life cycle . Furthermore, emodin has affinity for phospholipid membrane and is efficient in weakening hydrophobic interactions between hydrocarbon chains in phospholipid bilayers, contributing towards the antiviral capacity of emodin against enveloped viruses .
In this study, we demonstrated that emodin can exert its antiviral activity by the third mechanism, the inhibition PARP of HSV 1 UL12 alkaline Doxorubicin nuclease activity. These findings suggest that emodin could be a potential anti HSV 1 candidate having a broad spectrum of antiviral activities. Our results indicate that emodin inhibits HSV 1 UL12 activity, top towards the reduction of HSV 1 yields in Vero cells. How did emodin inhibit nuclease activity of HSV 1 UL12? To answer this question, we modelled the threedimensional structure of UL12 working with phage l exonuclease as the template protein. Although HSV 1 UL12 exhibits a low amino acid sequence similarity with l exonuclease, HSV 1 UL12 shares equivalent enzyme activities and biological functions with l exonuclease.
Decitabine For instance, both proteins preferentially degrade DNA from double stranded end in the 50 30 direction . Furthermore, they mediate DNA strand exchange by interacting with ssDNA binding protein and participate in initiating viral recombination events . The recognizable homology suggests that working with l exonuclease as the template for the modelling of UL12 is reasonable. The interaction of emodin with UL12 was predicted by docking analysis. Outcomes showed that emodin docked into UL12 but not bovine pancreatic DNase I . Emodin interacted with Asp 227, Trp 231, Val 273, Asp 340, Glu 364, Val 365 and Lys 366 of UL12 via hydrogen bonds or hydrophobic interactions. Interestingly, some of these amino acid residues could be critical for the nuclease activity.
Website directed mutagenesis on the HSV 1 UL12 homologue, Epstein Barr virus DNase, has revealed that Asp 203, Glu 225 and Lys 227 of Epstein Barr virus DNase, corresponding to Asp 340, Glu Doxorubicin 364 and Lys 366 of UL12, respectively, play crucial roles in catalysis . Glu 225 of Epstein Barr virus DNase, corresponding to Glu 364 of UL12, is involved in metal binding. The docking of emodin into UL12 could affect or occupy the catalytic website of UL12, top towards the inhibition of nuclease activity. Thus, the interaction between emodin and critical amino acid residues of UL12 could explain why emodin inhibited the nuclease activity of HSV 1 UL12. In conclusion, emodin significantly reduced the plaque formation in Vero cells. Serum profiles soon after oral administration of emodin at a dosage of 2 g kg 1 in mice showed that the peak serum concentration of emodin is 700 mM . We revealed that emodin at a concentration of 21.5 mM was sufficient to decrease 50 virus yields devoid of cytotoxic effec