title: Synthesis and in vitro testing of new potent polyacridine-melittin gene delivery peptides.
abstract: The combination of a polyacridine peptide modified with a melittin fusogenic peptide results in a potent gene transfer agent. Polyacridine peptides of the general formula (Acr-X)(n)-Cys were prepared by solid-phase peptide synthesis, where Acr is Lys modified on its epsilon-amine with acridine, X is Arg, Leu, or Lys and n is 2, 3, or 4 repeats. The Cys residue was modified by either a maleimide-melittin or a thiolpyridine-Cys-melittin fusogenic peptide resulting in reducible or non-reducible polyacridine-melittin peptides. Hemolysis assays established that polyacridine-melittin peptides retained their membrane lytic potency relative to melittin at pH 7.4 and 5. When combined with plasmid DNA, the membrane lytic potency of polyacridine-melittin peptides was neutralized. Gene transfer experiments in multiple cell lines established that polyacridine-melittin peptides mediate expression as efficiently as PEI. The expression was very dependent upon a disulfide bond linking polyacridine to melittin. The gene transfer was most efficient when X is Arg and n is 3 or 4 repeats. These studies establish polyacridine peptides as a novel DNA binding anchor peptide.
authors.affiliation: College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Baumhover
authors.forename: Kevin
authors.initials: K
authors.lastname: Anderson
authors.forename: Christian A
authors.initials: CA
authors.lastname: Fernandez
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Rice
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D018014:Gene Transfer Techniques; D006461:Hemolysis / Q000187:drug effects / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D008555:Melitten / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism
chemical_list: D000166:Acridines; D011108:Polymers; D013438:Sulfhydryl Compounds; D008555:Melitten; D004247:DNA; D001120:Arginine; D003545:Cysteine