Histidine-rich Modification of a Scorpion-derived Peptide Improves Bioavailability and Inhibitory Activity against HSV-1

Zeng, Zhengyang; Zhang, Runhong; Hong, Wei; Cheng, Yuting; Wang, Huijuan; Lang, Yange; Ji, Zhenglin; Wu, Yingliang; Li, Wenxin; Xie, Youli; Cao, Zhijian

It is worth noting that Eval418-FH5, in which the most histidine residues were introduced, exhibited a significantly reduced cytotoxicity compared with the other derivative peptides. The CC50 of Eval418-FH5 was 106.68 μg/mL, but the CC 50 of Eval418 was 68.50 μg/mL. Eval418-FH5 also showed a rapid action by clearing more than 50% of PFUs after incubation with HSV-1 for only 5 min. The IC 50 of Eval418-FH5 for HSV-1 inactivation and attachment were 0.86 and 0.67 μg/mL, respectively. Therefore, the SIs of Eval418-FH5 were significantly enhanced to 124.05 and 159.22, respectively, whereas those of the wild type peptide Eval418 were 27.62 and 18.51, respectively. The flow cytometry and confocal microscopy results showed that Eval418-FH5 exerted a considerable cellular uptake and a dispersed distribution, which may explain its superior antiviral activity in the presence of an established HSV-1 infection. Thus, the introduction of histidine residues into the hydrophilic face of Eval418 molecules can overcome barriers in cellular uptake, improve antiviral activity and therefore enable the Eval418 derivatives to interact with intracellular HSV-1.