Structure-activity relationship of truncated and substituted analogues of the intracellular delivery vector Penetratin

P. M. Fischer, N. Z. Zhelev, S. Wang, J. E. Melville, R. Fåhraeus, D. P. Lane

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Peptides derived from the third α-helix of the homeodomain (residues 43-58; Penetratin) of Antennapedia, a Drosophila homeoprotein, were prepared by simultaneous multiple synthesis. Sets of N- and C-terminally truncated peptides, as well as a series of alanine substitution analogues, were studied. Cell penetration assays using human cell cultures with these peptides revealed that the C-terminal segment 52Arg-Arg-Met-Lys-Trp-Lys- Lys58 of the parent sequence was necessary and sufficient for efficient cell membrane translocation. Individual Ala substitutions of the peptide's basic residues led to markedly decreased cell internalization ability, whereas replacement of hydrophobic residues was tolerated surprisingly well. Subcellular localization was seen to be affected by substitutions, with analogues being addressed preferentially to the cytosol or to the nucleus. Conformational constriction of the Penetratin sequence through placement and oxidation of flanking cysteine residues afforded a cyclic disulfide peptide which had lost most of its membrane translocation capacity.

Original languageEnglish
Pages (from-to)163-172
Number of pages10
JournalJournal of Peptide Research
Volume55
Issue number2
DOIs
Publication statusPublished - 15 Feb 2000
Externally publishedYes

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Structure-Activity Relationship
Peptides
Substitution reactions
Homeodomain Proteins
Cyclic Peptides
Constriction
Disulfides
Alanine
Cytosol
Drosophila
Cysteine
Cell Culture Techniques
Cell Membrane
Cell membranes
Membranes
Cell culture
Assays
penetratin
Oxidation

Cite this

Fischer, P. M. ; Zhelev, N. Z. ; Wang, S. ; Melville, J. E. ; Fåhraeus, R. ; Lane, D. P. / Structure-activity relationship of truncated and substituted analogues of the intracellular delivery vector Penetratin. In: Journal of Peptide Research. 2000 ; Vol. 55, No. 2. pp. 163-172.
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Structure-activity relationship of truncated and substituted analogues of the intracellular delivery vector Penetratin. / Fischer, P. M.; Zhelev, N. Z.; Wang, S.; Melville, J. E.; Fåhraeus, R.; Lane, D. P.

In: Journal of Peptide Research, Vol. 55, No. 2, 15.02.2000, p. 163-172.

Research output: Contribution to journalArticle

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AU - Fischer, P. M.

AU - Zhelev, N. Z.

AU - Wang, S.

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AU - Lane, D. P.

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AB - Peptides derived from the third α-helix of the homeodomain (residues 43-58; Penetratin) of Antennapedia, a Drosophila homeoprotein, were prepared by simultaneous multiple synthesis. Sets of N- and C-terminally truncated peptides, as well as a series of alanine substitution analogues, were studied. Cell penetration assays using human cell cultures with these peptides revealed that the C-terminal segment 52Arg-Arg-Met-Lys-Trp-Lys- Lys58 of the parent sequence was necessary and sufficient for efficient cell membrane translocation. Individual Ala substitutions of the peptide's basic residues led to markedly decreased cell internalization ability, whereas replacement of hydrophobic residues was tolerated surprisingly well. Subcellular localization was seen to be affected by substitutions, with analogues being addressed preferentially to the cytosol or to the nucleus. Conformational constriction of the Penetratin sequence through placement and oxidation of flanking cysteine residues afforded a cyclic disulfide peptide which had lost most of its membrane translocation capacity.

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