Zinc(II)-coordinated oligotyrosine: a new class of cell penetrating peptide.
A new series of cell penetrating peptides (CPPs) are described. The peptides are oligomers of Tyr-ZnDPA, a tyrosine derivative with an appended 2,2'-dipicolylamine unit that forms a very stable coordination complex with a zinc (II) cation. This in turn allows reversible association with a chelating oxyanion such as a carboxylate or phosphate derivative. The peptide oligomers (Tyr-ZnDPA) n where n = 1, 2, 4, 8, are highly water soluble, but upon association with fatty acids or phospholipids they partition into an organic octanol phase. Furthermore, a fluorescent, fluorescein-labeled version of the octamer, (Tyr-ZnDPA) 8-Fl, can enter living mammalian cells via endocytosis and a biotin derivative can deliver fluorescein-labeled streptavidin. Fluorescence microscopy and flow cytometry experiments show that cell uptake is diminished by conditions that inhibit endocytosis. Additionally, uptake of (Tyr-ZnDPA) 8-Fl is greater than fluorescein labeled octaarginine (Arg 8-Fl) in all cell lines tested (CHO, COS-7, HeLa). Another difference with Arg 8-Fl is that cell uptake of (Tyr-ZnDPA) 8-Fl does not require the presence of heparan sulfate proteoglycans on the cell surface. This difference may eventually be of practical value because drug delivery systems that employ alternative endocytic mechanisms may be optimal for different cell lines or they may deliver selectively to different organelles within a cell.
Johnson
James R
JR
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Jiang
Hua
H
Smith
Bradley D
BD
D000588:Amines / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002412:Cations / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010848:Picolinic Acids / Q000737:chemistry; D013237:Stereoisomerism; D019809:Streptavidin / Q000737:chemistry / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
C501847:2,2'-dipicolylamine; D000588:Amines; D002412:Cations; D004337:Drug Carriers; D009842:Oligopeptides; D009942:Organometallic Compounds; D010848:Picolinic Acids; D014443:Tyrosine; D019809:Streptavidin; D015032:Zinc