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

Various methods have been employed to overcome the limitations surrounding intracellular AMP antiviral activities. For example, addition of D-amino acids [29, 30] or fluorinated amino acids [31] may enhance peptide transmembrane delivery. The presence of lysosomotropic agents or introduction of histidine residues can enhance the transfection efficiencies of vehicle peptides as well as AMP cellular uptake and antiviral ability [16, [32] [33] [34] . In a previous study from our group, a glycine residue and a proline residue of the scorpion venom derived peptide mucroporin were replaced with a lysine residue and an arginine residue, respectively, to enhance the net positive charge of the hydrophilic side of the molecule. After the modifications, mucroporin-M1 exhibited a stronger virucidal activity and additional inhibition of HBV replication in vitro and in vivo [13, 14] . Ctry2459, another scorpion-derived peptide from the scorpion C. tryznai, has been modified into 2 histidine-rich mutant peptides to overcome the barriers of cellular uptake and endosome escape. These modifications significantly enhanced the anti-HCV activities and cellular uptake and introduced inhibition of established viral infection [16] .