title: Design of histidine-rich peptides with enhanced bioavailability and inhibitory activity against hepatitis C virus.
abstract: Recently, peptide drugs have evolved into mainstream therapeutics, representing a significant portion of the pharmaceutical market. However, their bioavailability remains to be improved compared with that of chemical drugs. Here, we screened and identified a new peptide, Ctry2459, from a scorpion venom peptide library that was proven to inhibit hepatitis C virus (HCV) infection via inactivating infectious viral particles. However, Ctry2459 cannot suppress established infection of HCV because of the poor cellular uptake and restriction of endosomes. Based on the molecular template of the Ctry2459 peptide, we designed two histidine-rich peptides (Ctry2459-H2 and Ctry2459-H3) with significantly enhanced cellular uptake and improved intracellular distribution. Moreover, the two mutated peptides, as well as the wild-type peptide Ctry2459, exhibited virucidal activities against HCV. In distinct contrast to the Ctry2459 peptide, the mutated peptides significantly suppressed the established HCV infection at the cellular level but demonstrated lower cytotoxic and hemolytic activities. Our work presents an effective design strategy for optimizing natural antiviral peptides and opens a new avenue for enhancing the bioavailability of peptide drugs.
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors: Wei
authors: W
authors: Hong
authors: Runhong
authors: R
authors: Zhang
authors: Zhiyong
authors: Z
authors: Di
authors: Yawen
authors: Y
authors: He
authors: Zhenhuan
authors: Z
authors: Zhao
authors: Jun
authors: J
authors: Hu
authors: Yingliang
authors: Y
authors: Wu
authors: Wenxin
authors: W
authors: Li
authors: Zhijian
authors: Z
authors: Cao
mesh_terms: D000143:Acids / Q000378:metabolism; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000821:virology; D015723:Gene Library; D006461:Hemolysis / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000821:virology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012604:Scorpion Venoms / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D038301:Virus Inactivation / Q000187:drug effects; D000099053:Histidine-Rich Glycoprotein
chemical_list: D000143:Acids; D000998:Antiviral Agents; D010455:Peptides; D011506:Proteins; D012604:Scorpion Venoms; D000099053:Histidine-Rich Glycoprotein; D006180:Proton-Translocating ATPases