Cell-penetrating peptides: From molecular mechanisms to therapeutics

Biology of the Cell

Volumn 100, Issue 4, 2008, Pages 201-217

  Morris, May C ^a   Deshayes, Sebastien ^a   Heitz, Frederic ^a   Divita, Gilles ^a  

^a CNRS   (France)

Author keywords

Cell penetrating peptide (CPP); Drug delivery; Nanoparticle; Non covalent delivery system; Short interfering RNA (siRNA)

Indexed keywords

4 HYDROXYL PROLINE PHOSPHONATE PEPTIDE NUCLEIC ACID; ANTIBODY; ANTISENSE OLIGONUCLEOTIDE; CARRIER PROTEIN; CELL PENETRATING PEPTIDE; GLYCYLALANYLLEUCYLPHENYLALANYLLEUCYLGLYCYLPHENYLALANYLLEUCYLGLYCYLALANYLALANYLGLYCYLSERYLTHREONYLMETHIONYLGLYCYLALANYLTRYPTOPHANYLSERYLGLUTAMYLPROLYLLYSYLSERYLLYSYLARGINYLLYSYLVALINE; LYSYLGLUTAMYLTHREONYLTRYPTOPHANYLTRYPTOPHANYLGLUTAMYLTHREONYLTRYPTOPHANYLTRYPTOPHANYLTHREONYLGLUTAMYLTRYPTOPHANYLSERYLGLUTAMINYLLYSYLLYSYLLYSYLARGINYLLYSYLVALINE; MACROGOL; NANOPARTICLE; NUCLEIC ACID; PEPTIDE DERIVATIVE; PEPTIDE NUCLEIC ACID; PLASMID DNA; PROTEOGLYCAN; SMALL INTERFERING RNA; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; BIOCOMPATIBILITY; BIODEGRADABILITY; BIOLOGICAL ACTIVITY; CELL COMPARTMENTALIZATION; CELL TRANSPORT; CONTROLLED DRUG RELEASE; CYTOTOXICITY; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG FORMULATION; DRUG MEGADOSE; DRUG STABILITY; DRUG TARGETING; EXPRESSION VECTOR; GENE EXPRESSION; GENETIC TRANSDUCTION; HUMAN; HYDROPHILICITY; HYDROPHOBICITY; MOLECULAR MECHANICS; MOLECULAR MIMICRY; NANOTECHNOLOGY; NONHUMAN; NONVIRAL GENE DELIVERY SYSTEM; NUCLEAR LOCALIZATION SIGNAL; PARTICLE SIZE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FAMILY; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; STRUCTURE ACTIVITY RELATION; SYSTEMIC THERAPY;

AMINO ACID SEQUENCE; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG CARRIERS; DRUG DELIVERY SYSTEMS; HUMANS; MOLECULAR SEQUENCE DATA; NANOPARTICLES; OLIGOPEPTIDES; PEPTIDE NUCLEIC ACIDS; PEPTIDES; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 42049095153     PISSN: 02484900     EISSN: None     Source Type: Journal    
DOI: 10.1042/BC20070116     Document Type: Review

References (158)

1. Abes, S., Turner, J., Ivanova, G.D., Owen, D., Williams, D., Arzumanov, A., Clair, P., Gait, M.J. and Lebleu, B. (2007) Efficient splicing correction by PNA conjugation to an R6-penetratin delivery peptide. Nucleic Acids Res. 35, 4495-4502
2. Aoshiba, K., Yokohori, N. and Nagal, A. (2003) Alveolar wall apoptosis causes lung destruction and amphysematous changes. Am. J. Respir. Cell Mol. Biol. 28, 555-561
3. Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., Yang, R., Petasis, N.A. and Serhan, C.N. (2005) Stereochemical assignment, anti-inflammatory properties and receptors for the omega-3 lipid mediator resolving E1. J. Exp. Med. 201, 713-722
4. Asai, A., Oshima, Y., Yamamoto, Y., Uochi, T.A., Kusaka, H., Akinaga, S., Yamashita, Y., Pongracz, K., Pruzan, R., Wunder, E., Piatyszek, M., Li, S., Chin, A.C., Harley, C.B. and Gryaznov, S. (2003) A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. 63, 3931-3939
5. Badag-Gorce, F., Riley, N., Nguyen, V., Montgomery, R.O., French, B.A., Li, F.W., Van Leeuwen, W., Lungo, L.W., McPhaul, L.W. and French, S.W. (2003) The mechanism of cytokeratin aggresome formation: the role of mutant ubiquitin (UBB1). Exp. Mol. Pathol. 74, 160-167
6. Balali-Mood, K., Ashley, R.H., Hauss, T. and Bradshaw, J.P. (2005) Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin. FEBS Left. 579, 1143-1148
7. Beauvais, D.M. and Rapraeger, A.C. (2004) Syndecans in tumor cell adhesion and signalling. Reprod. Biol. Endocrinol. 2, 3-5
8. Belting, M. and Petersson, P. (1999) Intracellular accumulation of secreted proteoglycans inhibits cationic lipid-mediated gene transfer. Co-transfer of glycosaminoglycans to the nucleus. J. Biol. Chem. 274, 19375-19382
9. Bjorklund, J., Biverstahl, H., Graslund, A., Maler, L. and Brzezinski, P. (2006) Real-time transmembrane translocation of penetratin driven by light-generated proton pumping. Biophys. J. 291, 29-31
10. Branden, L.J., Mohamed, A.J. and Smith, C.I. (1999) A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA. Nat. Biotechnol. 17, 784-787
11. Brummelkamp, T.R., Bernards, R. and Agami, R. (2002) Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243-251
12. Burlina, F., Sagan, S., Bolbach, G. and Chassaing, G. (2006) A direct approach to quantification of the cellular uptake of cell-penetrating peptides using MALDI-TOF mass spectrometry. Nat. Protoc. 1, 200-205
13. Cartier, R. and Reszka, R. (2002) Utilization of synthetic peptides containing nuclear localization signals for nonviral gene transfer systems. Gene Ther. 9, 157-163
14. Chan, S.A., Polo-Parada, L., Landmesser, L.T. and Smith, C. (2005) Adrenal chromaffin cells exhibit impaired granule trafficking in NCAM knockout mice, J. Neurophysiol. 94, 1037-1047
15. Chiang, C.M., Chien, K.Y., Lin, H.J., Lin, J.F., Yeh, H.C., Ho, P.L. and Wu, W.G. (1996) Conformational change and inactivation of membrane phospholipid-related activity of cardiotoxin V from Taiwan cobra venom at acidic pH. Biochemistry 35, 9167-9176
16. Conner, S.D. and Schmid, S.L. (2003) Regulated portals of entry into the cell. Nature 422, 37-44
17. Console, S., Marty, C., Garcia-Echeverria, C., Schwendener, R. and Ballmer-Hofer, K. (2003) Antennapedia and HIV transactivator of transcription (TAT) 'protein transduction domains' promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans, J. Biol. Chem. 278, 35109-35114
18. Couchman, J.R. (2003) Syndecans: proteoglycan regulators of cell-surface microdomains? Nat. Rev. Mol. Cell Biol. 4, 926-937
19. Crombez, L., Charnet, A., Morris, M.C., Aldrian-Herrada, G., Heitz, F. and Divita, G. (2007) A non-covalent peptide-based strategy for siRNA delivery. Biochem. Soc. Trans. 35, 44-46
20. Davidson, T.J., Harel, S., Arboleda, V.A., Prunell, G.F., Shelanski, M.L., Greene, L.A. and Troy, C.M. (2004) Highly efficient small interfering RNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation. J. Neurosci. 10, 10040-10046
21. De Fougerolles, A., Vornlocher, H.-P., Maraganore, J. and Lieberman, J. (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat. Rev. Drug Discov. 6, 443-453
22. Dehio, C., Freissler, E., Lanz, C., Gomez-Duarte, O.G., David, G. and Meyer, T.F. (1998) Ligation of cell surface heparan sulphate proteoglycans by antibody-coated beads stimulates phagocytic uptake into epithelial cells: a model for cellular invasion by Neisseria gonorrhoeae. Exp. Cell Res. 242, 528-539
23. Derossi, D., Joliot, A.H., Chassaing, G. and Prochiantz, A. (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269, 10444-10450
24. Deshayes, S., Heitz, A., Morris, M.C., Charnet, P., Divita, G. and Heitz, F. (2004a) Insight into the mechanism of internalization of the cell-penetrating carrier peptide Pep-1 through conformational analysis. Biochemistry 43, 1449-1457
25. Deshayes, S., Gerbal-Chaloin, S., Morris, M.C., Aldrian-Herrada, G., Charnet, P., Divita, G. and Heitz, F. (2004b) On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids. Biochim. Biophys. Acta 1667, 141-147
26. Deshayes, S., Plenat, T., Aldrian-Herrada, G., Divita, G., LeGrimellec, C. and Heitz, F. (2004c) Primary amphipathic cell-penetrating peptides: structural requirements and interactions with model membranes. Biochemistry 43, 7698-7706
27. Deshayes, S., Morris, M.C., Divita, G. and Heitz, F. (2005) Cell-penetrating peptides: tools for intracellular delivery of therapeutics. Cell Mol. Life Sci. 62, 1839-1849
28. Deshayes, S., Plánat, T., Charnet, P., Divita, G., Molle, G. and Heitz, F (2006) Formation of transmembrane ionic channels of primary amphipathic cell-penetrating peptides. Consequences on the mechanism of cell penetration. Biochim. Biophys. Acta 1758, 1846-1851
29. Deshayes, S., Morris, M.C., Divita, G. and Heitz, F (2007) Interaction of cell penetrating peptide with model membrane. In Cell-Penetrating Pepticles (Langel, Ü., ed.), 2nd edn, pp. 139-160, CRC Press, Boca Raton
30. Dorsett, Y. and Tiuschl, T. (2004) siRNAs: applications in functional genomics and potential as therapeutics. Nat. Rev. Drug Discov. 3, 318-329
31. Efimov, V., Choob, M., Buryakova, A., Phelan, D. and Chakhmakhcheva, O. (2001) PNA-related oligonucleotide mimics and their evaluation for nucleic acid hybridization studies and analysis. Nucleosides Nucleotides Nucleic Acids 20, 419-428
32. Eitzen, G. (2003) Actin remodelling to facilitate membrane fusion. Biochim. Biophys. Acta 1641, 175-181
33. El-Andaloussi, S., Holm, T. and Langel, Ü. (2005) Cell-penetrating peptides: mechanism and applications. Curr. Pharm. Design 11, 3597-3611
34. Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K. and Tiuschl, T. (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498
35. Elliott, G. and O'Hare, R (1997) Intercellular trafficking and protein delivery by a Herpesvirus structural protein. Cell 88, 223-233
36. Esbjorner, E.K., Gräslung, A. and Nordën, P. (2007) Membrane interactions of cell-penetrating peptides. In Cell-Penetrating Peptides (Langel, Ü., ed.), 2nd edn, pp. 109-138, CRC; Press, Boca Raton
37. Esclatine, A., Bellon, A., Michelson, S., Servin, A.L., Quero, A.M. and Geniteau-Legendre, M. (2001) Differentiation-dependent redistribution of heparan sulfate in epithelial intestinal Caco-2 cells leads to basolateral entry of cytomegalovirus. Virology 289, 23-33
38. Escriou, V., Carriere, M., Scherman, D. and Wils, P. (2003) NLS bioconjugates for targeting therapeutic genes to the nucleus. Adv. Drug Deliv. Rev. 55, 295-306
39. Eum, W.S., Kim, D.W., Hwang, I.K., Yoo, K.Y., Kang, T.C., Jang, S.H., Choi, H.S., Choi, S.H., Kim, Y.H., Kim, S.Y., Kwon, H.Y., Kang, J.H., Kwon, O.S., Cho, S.W., Lee, K.S., Park, J., Won, M.H. and Choi, S.Y. (2004) In vivo protein transduction: biologically active intact pep-1-superoxide dismutase fusion protein efficiently protects against ischemic insult. Free Radical Biol. Med. 37, 1656-1669
40. Fawell, S., Seery, J., Daikh, Y., Moore, C., Chen, L.L., Pepinsky, B. and Barsourn, J. (1994) Tat-mediated delivery of heterologous proteins into cells. Proc. Natl. Acad. Sci. U.S.A. 91, 664-668
41. Fischer, R., Fotin-Mleczek, M., Hufnagel, H. and Brock, R. (2005) Break on through to the other side-biophysics and cell biology shed light on cell-penetrating peptides. Chembiochem 6, 2126-2142
42. Fountaine, T.M., Wood, M.J. and Wade-Martins, R. (2005) Delivering RNA interference to the mammalian brain. Curr. Gene Ther. 5, 399-410
43. Frankel, A.D. and Pabo, C.O. (1998) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55, 1189-1193
44. Futaki, S., Suzuki, T., Ohashi, W., Yagami, T., Tanaka, S., Ueda, K. and Sugiura, Y. (2001) Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J. Biol. Chem, 276, 5836-5840
45. Gait, M.J. (2003) Peptide-mediated cellular delivery of antisense oligonucleoticles and their analogues. Cell. Mol. Life Sci. 60, 844-853
46. Gallo, G., Yee, H.F. and Letourneau, P.C. (2002) Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility. J. Cell Biol. 158, 1219-1228
47. Gallo, G. (2003) Making proteins into drugs: assisted delivery of proteins and peptides into living neurons. Methods Cell Biol. 71, 325-338
48. Gariepy, J. and Kawamura, K. (2000) Vectorial delivery of macromolecules into cells using peptide-based vehicles. Trends Biotechnol. 19, 21-26
49. Garnon, J., Lachance, C., Di Marco, S., Hel, Z., Marion, D., Ruiz, M.C., Newkirk, M.M., Khandjian, F.W. and Radzioch, D. (2005) Fragile X-related protein FXR1P regulates proinflammatory cytokine TNF expression at the post-transcriptional level. J. Biol. Chem. 280, 5750-5763
50. Gehler, S., Shaw, A.E., Sarmiere, P.D., Bamburg, J.R. and Letourneau, PC. (2004) Brain-derived neutrophic factor regulation of retinal growth cone filopodial dynamics is mediated through actin depolymerizing factor/ cofilin. J. Neurosci. 24, 10741-10749
51. Gerbal-Chaloin, S., Gondeau, C., Aldrian-Herrada, G., Heitz, F., Gauthier-Rouvière, C. and Divita, G. (2007) First step of the cell-penetrating peptide mechanism involves Rac1 GTPase-dependent actin-network remodelling. Biol. Cell 99, 223-238
52. Glover, D.J., Lipps, H.J. and Jans, D.A. (2005) Towards safe, non-viral therapeutic gene expression in humans. Nat. Rev. Genet. 6, 299-310
53. Gros, E., Deshayes, S., Morris, M.C., Aldrian-Herrada, G., Depollier, J., Heitz, F, and Divita, G. (2006) A non-covalent peptide-based strategy for protein and peptide nucleic acid delivery. Biochim. Biophys. Acta 1758, 384-393
54. Gryaznov, S., Asai, A., Oshima, Y., Yamamoto, Y., Pongracz, K., Pruzan, R., Wunder, E., Piatyszek, M., Li, S., Chin, A., Harley, C., Akinaga, S. and Yamashita, Y. (2003) Oligonucleotide N3'→P5' thio-phosphoramidate telomerase template antagonists as potential anticancer agents. Nucleosides Nucleotides Nucleic Acids 22, 577-581
55. Hannon, G.J. (2002) RNA interference. Nature 418, 244-251
56. Hommel, J.D., Sears, R.M., Georgescu, D., Simmons, D.L. and DiLeone, R.J. (2003) Local gene knockdown in the brain using viral-mediated RNA interference. Nat. Med. 9, 1539-1544
57. Ignatovich, I.A., Dizhe, E.B., Pavlotskaya, A.V., Akifiev, B.N., Burov, S.V., Orlov, S.V. and Perevozchikov, A.P. (2003) Complexes of plasmid DNA with basic domain 47-57 of the HIV-1 Tat protein are transferred to mammalian cells by endocytosis-mediated pathways. J. Biol. Chem. 278, 42625-42636
58. Järver, P. and Langel, Ü. (2004) The use of cell-penetrating peptides as a toll for gene regulation. Drug Discov. Today 9, 395-402
59. Jevsek, M., Jaworski, A., Polo-Parada, L., Kim, N., Fan, J., Landmesser, L.T. and Burden, S.J. (2006) CD24 is expressed by myofiber synaptic and regulates synaptic transmission. Proc. Natl. Acad. Sci. U.S.A. 103, 6374-6379
60. Joliot, A. and Prochiantz, A. (2004) Transduction peptides: from technology to physiology. Nat. Cell Biol. 6, 189-196
61. Kaplan, I.M., Wadia, J.S. and Dowdy, S.F. (2005) Cationic Tat peptide transduction domain enters cells by macropinocytosis. J. Control. Release 102, 247-253
62. Kim, W.J., Christensen, L.V., Jo, S., Yockman, J.W., Jeong, J.H., Kim, Y.H. and Kim, S.W. (2006) Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. Mol. Ther. 14, 343-350
63. Kong, H.J. and Mooney, D.J. (2007) Microenvironmental regulation of biomacromolecular therapies. Nat. Rev. Drug Discov. 6, 455-463
64. Koppelhus, U. and Nielsen, P.E. (2003) Cellular delivery of peptide nucleic acid. Adv. Drug. Deliv. Rev. 55, 267-280
65. Kowolik, C.M., Yam, P., Yu, Y. and Yee, J.K. (2003) HIV vector production mediated by Rev protein transduction. Mol. Ther. 2, 324-331
66. Krauss, U., Muller, M., Stahl, M. and Beck-Sickinger, A.G. (2004) In vitro gene delivery by a novel human calcitonin (hCT)-derived carrier peptide. Bioorg. Med. Chem. Lett. 14, 51-54
67. Kumar, P., Wu, H., McBride, J.L., Jung, K.E., Kim, M.H., Davidson, B.L., Lee, S.K., Shankar, P. and Manjunath, N. (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448, 39-43
68. Labialle, S., Dayan, G., Gayet, L., Rigal, D., Gambrelle, J. and Baggetto, L.G. (2004) New invMED1 element cis-activates human multidrug-related MDR1 and MVP genes, involving the LRP130 protein. Nucleic Acids Res. 32, 3864-3876
69. Langel, Ü. (2007) Cell-Penetrating Peptides: Processes and Applications, Pharmacology and Toxicology series, CRC Press, Boca Raton
70. Langlois, M.A., Boniface, C., Wang, G., Alluin, J., Salvaterra, P.M., Puymirat, J., Rossi, J.J. and Lee, N.S. (2005) Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. J. Biol. Chem. 280, 16949-16954
71. Letoha, T, Gaal, S., Somlai, C., Czajlik, A., Perczel, A. and Penke, B. (2003) Membrane translocation of penetratin and its derivatives in different cell lines. J. Mol. Recognit. 16, 272-279
72. Lewis, D.L., Hagstrom, J.E., Loomis, A.G., Wolff, J.A. and Herweijer, H. (2002) Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat. Genet. 32, 107-108
73. Li, Y., Heitz, F., Le Grimellec, C. and Cole, R.B. (2005) Fusion peptide-phospholipid noncovalent interactions as observed by nanoelectrospray FTICR-MS. Anal. Chem. 77, 1556-1565
74. Lundberg, M. and Johansson, M. (2001) Is VP22 nuclear homing an artefact? Nat. Biotechnol. 19, 713-714
75. Lundberg, M., Wikstrom, S. and Johansson, M. (2003) Cell surface adherence and endocytosis of protein transduction domain. Mol. Ther. 8, 143-150
76. Lundberg, P., El-Andaloussi, S., Sutlu, T., Johansson, H. and Langel, U. (2007) Delivery of short interfering RNA using endosomolytic cell-penetrating peptides. FASEB J. 11, 2664-2671
77. Magzoub, M. and Gräslund, A. (2004) Cell-penetrating peptides: small from inception to application. Q. Rev. Biophys. 37, 147-195
78. Maron, M.B, Folkesson, H.G., Stader, S.M. and Walro, J.M. (2005) PKA delivery to the distal lung air spaces increases alveolar liquid clearance after isoproterenol-induced alveolar epithelial PKA desensitization. Am. J. Physiol. Lung Cell. Mol. Physiol. 289, L349-L354
79. Marthinet, E., Divita, G., Bernaud, J., Rigal, D. and Baggetto, L.G. (2000) Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter. Gene Ther. 7, 1224-1233
80. Mattheakis, L.C., Dias, J.M., Choi, Y.J., Gong, J., Bruchez, M.P, Liu, J. and Wang, E. (2004) Optical coding of mammalian cells using semiconductor quantum dots. Anal. Biochem. 327, 200-208
81. McCaffrey, A.P., Meuse, L., Pham, T.T., Conklin, D.S., Hannon, G.J. and Kay, M.A. (2002) RNA interference in adult mice. Nature 418, 38-39
82. McManus, M.T. and Sharp, P.A. (2002) Gene silencing in mammals by small interfering RNAs. Nat. Rev. Genet. 3, 737-747
83. Meade, B.R. and Dowdy, S.F. (2007) Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv. Drug Deliv. Rev. 59,134-140
84. Mery, J., Granier, C., Juin, M. and Brugidou, J. (1993) Disulfide linkage to polyacrylic resin for automated Fmoc peptide synthesis. Immunochernical applications of peptide resins and mercaptoamide peptides. Int. J. Pept. Protein Res. 42, 44-52
85. Morris, M.C., Vidal, P., Chaloin, L., Heitz, F. and Divita, G. (1997) A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res. 25,2730-2736
86. Morris, M.C., Chaloin, L., Mery, J., Heitz, F and Divita, G. (1999a) A novel potent strategy for gene delivery using a single peptide vector as a carrier. Nucleic Acids Res. 27, 3510-3517
87. Morris, M.C., Robert-Hebmann, V., Chaloin, L., Mery, J., Heitz, F., Devaux, C., Goody, R.S. and Divita, G. (1999b) A new potent HIV-reverse transcriptase inhibitor: a synthetic peptide derived from interface subunit domains. J. Biol. Chem. 274, 24941-24946
88. Morris, M.C., Chaloin, L., Heitz, F. and Divita, G. (2000) Translocating peptides and proteins and their use for gene delivery. Curr. Opin. Biotechnol. 11, 461-466
89. Morris, M.C., Depollier, J., Mery, J., Heitz, F. and Divita, G. (2001) A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat. Biotechnol. 19, 1173-1176
90. Morris, M.C., Chaloin, L., Choob, M., Archdeacon, J., Heitz, F. and Divita, G. (2004a) Combination of a new generation of PNAs with a peptide-based carrier enables efficient targeting of cell cycle progression. Gene Ther. 11, 757-764
91. Morris, K.V., Chan, S.W., Jacobsen, S.E. and Looney, D.J. (2004b) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305, 1289-1292
92. Morris, M.C., Depollier, J., Mery, J., Heitz, F and Divita, G. (2006) A peptide carrier for the delivery of biologically active proteins into mammalian cells: application to the delivery of antibodies and therapeutic proteins. In Cell Biology: A Laboratory Handbook (Celis, J.E., ed.), vol. 4, pp. 13-18, Elsevier Academic Press
93. Morris, M.C., Deshayes, S.Simeoni, F. Aldrian-Herrada, G., Heitz, F. and Divita, G. (2007a) A noncovalent peptide-based strategy for peptide and short interfering RNA delivery. In Cell-Penetrating Peptides (Langel, Ü., ed.), 2nd edn, pp. 387-408, CRC press, Boca Raton
94. Morris, M.C., Gros, E., Aldrian-Herrada, G., Choob, M., Archdeacon, J., Heitz, F. and Divita, G. (2007b) A non-covalent peptide-based carrier for in vivo delivery of DNA mimics. Nucleic Acids Res. 35, e49-e59
95. Moschos, S., Williams, A. and Lindsay, M. (2007) In vivo applications of cell-penetrating peptide. In Cell-Penetrating Peptides (Langel, Ü., ed.), 2nd edn, pp. 423-438, CRC Press, Boca Raton
96. Moulton, H.M. and Moulton, J.D. (2004) Arginine-rich cell-penetrating peptides with uncharged antisense oligomers. Drug Discov. Today 9, 870-875
97. Munoz-Morris, M.A., Heitz, F, Divita, G. and Morris, M.C. (2007) The peptide carrier Pep-1 forms biologically efficient nanoparticle complexes, Biochem. Biophys. Res. Commun. 355, 877-882
98. Muratovska, A. and Eccles, M.R. (2004) Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Left. 558, 63-68
99. Murriel, C.L and and Dowdy, S.F. (2006) Influence of protein transduction domains on intracellular delivery of macromolecules. Expert Opin. Drug Deliv. 3, 739-746
100. kip1 induced cell migration. Nat. Med. 4, 1449-1452
101. Nakase, I., Niwa, M., Takeuchi, I, Sonomura, K., Kawabata, N., Koike, Y, Takehashi, M., Tanaka, S., Ueda, K., Simpson, J.C., Jones, A.T., Sugiura, Y. and Futaki, S. (2004) Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. Mol. Ther. 10, 1011-1022
102. Nakase, I., Tadokoro, A., Kawabata, N., Takeuchi, T., Katoh, H., Hiramoto, K., Negishi, M., Nomizu, M., Sugiura, Y. and Futaki, S. (2007) Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry 46, 492-450
103. Nan, L., Wu, Y, Bardag-Gorce, F, Li, J., French, BA., Wilson, L., Khanh, S., Nguyen, T. and French, S.W. (2005) RNA interference of VCP/p97 increases Mallory body formation. Exp. Mol. Pathol. 78, 1-9
104. Nguyen, Q.N., Chavli, R.V., Marques, J.T., Jr, Conrad, P.G., Wang, D., He, W., Belisle, B.E., Zhang, A., Pastor, L.M., Witney, F.R., Morris, M., Heitz, F, Divita, G., Williams, R. and McMaster, G.K. (2006) Light controllable siRNAs regulate gene suppression and phenotypes in cells. Biochim. Biophys. Acta 1758, 394-403
105. Niidome, T. and Huang, L. (2002) Gene therapy progress and prospects: non viral vectors. Gene Ther. 10, 1647-1652
106. Nordera, R, Serra, M.D. and Menestrina, G. (1997) The adsorption of Pseudomonas aeruginosa exotoxin A to phospholipid monolayers is controlled by pH and surface potential. Biophys. J. 73, 1468-1478
107. Ogris, M. and Wagner, E. (2002) Targeting tumors with non-viral gene delivery systems. Drug Discov. Today 7, 479-485
108. Opalinska, J.B. and Gewirtz, A.M. (2002) Nucleic-acid therapeutics: basic principles and recent applications. Nucleic-acid therapeutics: basic principles and recent applications. Nat. Rev. Drug Discov. 1, 503-514
109. Padari, K., Säälik, P., Hansen, M., Koppel, K., Raid, R., Langel, U. and Pooga, M. (2005) Cell transduction pathways of transportans. Bioconjug. Chem. 16, 1399-1410
110. Palm, C., Jayamanne, M., Kjellander, M. and Hällbrink, M. (2007) Peptide degradation is a critical determinant for cell-penetrating pepetide uptake. Biochim. Biophys. Acta 1768, 1769-1776
111. Pandey, A.V., Mellon, S.H. and Miller, W.L. (2003) Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J. Biol. Chem. 278, 2837-2844
112. Park, C.B., Yi, K.S., Matsuzaki, K., Kim, M.S. and Kim, S.C. (2000) Structure-activity analysis of buforin II, a histone H2A-derived antimicrobial peptide: the proline hinge is responsible for the cell-penetrating ability of buforin II. Proc. Natl. Acad. Sci. U.S.A. 97, 8245-8250
113. Pastor, L., Chavli, R., Divita, G., He, W., Heitz, F, McMaster, G., Morris, M., Nguyen, Q., Simeoni, F. and Zhang, A. (2006) Transfection of differentiated 3T3-L1 adipocytes using DeliverX Plus siRNA reagent solution. Application Note, http://www.panomics.com/ product.php?product_id=42
114. Payne, C., Rawe, V., Ramalho-Santos, J., Simerly, C. and Schatten, G. (2003) Preferentially localized dynein and perinuclear dynactin associate with nuclear pore complex proteins to mediate genomic union during mammalian fertilization. J. Cell Sci. 116, 4727-4738
115. Pichon, C., Monsigny, M. and Roche, A.C. (1999) Intracellular localization of oligonucleotides: influence of fixative protocols. Antisense Nucleic Acid Drug Dev. 9, 89-93
116. Plenat, T, Deshayes, S., Boichot, S., Milhiet, P.E., Cole, R., Heitz, F. and Le Grimellec, C. (2004) Interaction of primary amphipathic cell-penetrating peptides with phospholipid-supported monolayers. Langmuir 20, 9255-9261
117. Pooga, M., Soomets, U., Hallbrink, M., Valkna, A., Saar, K., Rezaei, K., Kahl, U., Hao, J.X., Xu, X.J., Wiesenfeld-Hallin, Z., Hokfelt, T., Bartfai, I and Langel, U. (1998) Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat. Biotechnol. 16, 857-861
118. Pooga, M., Kut, C., Kihlmark, M., Hallbrink, M., Fernaeus, S., Raid, R., Land, T, Hallberg, E., Bartfai, T and Langel, U. (2001) Cellular translocation of proteins by transportan. FASEB J. 8, 1451-1453
119. Pratt, R.L. and Kinch, M.S. (2002) Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade. Oncogene 21, 7690-7699
120. Pujals, S., Fernandez-Carneado, J., Lopez-Iglesias, C., Kogan, M.J. and Giralt, E. (2006) Mechanistic aspects of CPP-mediated intracellular drug delivery: relevance of CPP self-assembly. Biochim. Biophys. Acta 1758, 264-279
121. Rawe, V.Y., Payne, C., Navara, C. and Schatten, G. (2004) WAVE1 intranuclear trafficking is essential for genomic and cytoskeletal dynamics during fertilization: cell-cycle-dependent shuttling between M-phase and interphase nuclei. Dev. Biol. 276, 253-267
122. Richard, J.P., Melikov, K., Vives, E., Ramos, C., Verbeure, B., Gait, M.J., Chernomordik, L.V. and Lebleu, B. (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J. Biol. Chem. 278, 585-590
123. Richard, J.P., Melikov, K., Brooks, H., Prevot, R, Lebleu, B. and Chernomordik, V. (2005) Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J. Biol. Chem. 280, 15300-15306
124. Rittner, K., Benavente, A., Bompard-Sorlet, A., Heitz, F., Divita, G., Brasseur, R. and Jacobs, E. (2002) New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. Mol. Ther. 5, 104-114
125. Rothbard, J.B., Jessop, T.C., Lewis, R.S., Murray, B.A. and Wender, P.A. (2004) Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J. Am. Chem. Soc. 126, 9506-9507
126. Rudolph, C., Plank, C., Lausier, J., Schillinger, U., Muller, R.H. and Rosenecker, J. (2003) Oligomers of the arginine-rich motif of the HIV-1 TAT protein are capable of transferring plasmid DNA into cells. J. Biol. Chem. 278, 11411-11418
127. Rusnati, M., Tulipano, G., Spillmann, D., Tanghetti, E., Oreste, R, Zoppetti, G., Giacca, M. and Presta, M. (1999) Multiple interactions of HIV-I Tat protein with size-defined heparin oligosaccharides. J. Biol. Chem. 274, 28198-28205
128. Säälik, R, Elmquist, A., Hansen, M., Padari, K., Saar, K., Viht, K., Langel, U. and Pooga, M. (2004) Protein cargo delivery properties of cell-penetrating peptides. A comparative study. Bioconjug. Chem. 15, 1246-1253
129. Saoncella, S., Echtermeyer, F., Denhez, F, Nowlen, J.K., Mosher, D.F., Robinson, S.D., Hynes, R.O. and Goetinck, P.F. (1999) Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers. Proc. Natl. Acad. Sci. U.S.A. 96, 2805-2810
130. Schmidt, M.C., Rothen-Rutishauser, B., Rist, B., Beck-Sickinger, A., Wunderli-Allenspach, H., Rubas, W., Sadee, W. and Merkle, H.P. (1998) Translocation of human calcitonin in respiratory nasal epithelium is associated with self assembly in lipid membrane. Biochemistry 37, 16582-16590
131. Schwarze, S.R., Ho, A., Vocero-Akbani, A. and Dowdy, S.F. (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569-1572
132. Simeoni, F., Morris, M.C., Heitz, F. and Divita, G. (2003) Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res. 31, 2717-2724
133. Simeoni, F., Morris, M.C., Heitz, F. and Divita, G. (2005) Peptide-based strategy for siRNA delivery into mammalian cells. Methods Mol. Biol. 309, 261-264
134. Snyder, E.L. and Dowdy, S.F. (2005) Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo. Expert Opin. Drug Deliv. 2, 43-51
135. Song, E., Lee, S.K., Wang, J., Ince, N., Ouyang, N., Min, J., Chen, J., Shankar, P. and Lieberman, J. (2003) RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med. 9, 347-351
136. Song, E., Zhu, R, Lee, S.K., Chowdhury, D., Kussman, S., Dykxhoorn, D.M., Feng, Y., Palliser, D., Weiner, D.B., Shankar, P., Marasco, W.A. and Lieberman, J. (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 23, 709-717
137. Soutschek, J., Akinc, A., Bramlage, B., Charisse, K., Constien, R., Donoghue, M., Elbashir, S., Geick, A., Hadwiger, P., Harborth, J., John, M., Kesavan, V., Lavine, G., Pancley, R.K., Racie, T., Rajeev, K.G., Röhl, I., Toudjarska, I., Wang, G., Wuschko, S., Burncrot, D., Koteliansky, V., Limmer, S., Manolharan, M. and Vornlocher, H.P. (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173-178
138. Takeshita, F., Minakuchi, Y., Nagahara, S., Honma, K., Sasaki, H., Hirai, K., Teratani, T., Namatame, N., Yamamoto, Y., Hanai, K., Kato, T., Sano, A. and Ochiya., T. (2005) Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc. Natl. Acad. Sci. U.S.A. 102, 12177-12182
139. Tang, X., Molina, M. and Amar, S. (2007) p53 short peptide regulateds lipopolysaccharide -induced tumor necrosis factor-a-factor/cytokine expression. Cancer Res. 67, 1308-1316
140. Tatulian, S. and Tamm, L. (2000) Secondary structure, orientation, oligomerization, and lipid interactions of the transmembrane domain of influenza hemagglutinin. Biochemistry 39, 496-507
141. Terrone, D., Sang, S.L., Roudaia, L. and Silvius, J.R. (2003) Penetratin and related cell-penetrating cationic peptides can translocate across lipid bilayers in the presence of a transbilayer potential. Biochemistry 42, 13787-13799
142. Thomas, A., Deshayes, S., Decaffmeyer, M., Van Eyck, M.H., Charloteaux, B. and Brasseur, R. (2006) Prediction of peptide structure: how far are we? Proteins 65, 889-897
143. Thoren, P.E., Persson, D., Isakson, P., Goksor, M., Onfelt, A. and Norden, B. (2003) Uptake of analogs of penetratin, Tat(48-60) and oligoarginine in live cells. Biochem. Biophys. Res. Commun. 307, 100-107
144. Torchilin, V.P. (2005) Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4, 145-160
145. Tung, C.H., Mueller, S. and Weissleder, R. (2002) Novel branching membrane translocational peptide as gene delivery vector. Bioorg. Med. Chem. 10, 3609-3614
146. Van Mau, N., Vié, V, Chaloin, L., Lesniewska, E., Heitz, F and Le Grimellec, C. (1999) Lipid induced organization of a primary amphipathic peptide. A coupled AFM-monolayer study. J. Membr. Biol. 167, 241-249
147. Veldhoen, S., Laufer, S.D., Trampe, A. and Restle, T. (2006) Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating pepticle: quantitative analysis of uptake and biological effect. Nucleic Acids Res. 34, 6561-6573
148. Verger, R. and Pattus, F. (1976) Spreading of membranes at the air/water interface. Chem. Phys. Lipids 16, 285-291
149. Vives, E., Brodin, R and Lebleu, B. (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 272, 16010-16017
150. Wadia, J., Stan, R.V. and Dowdy, S. (2004) Transclucible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat. Med. 10, 310-315
151. Wender, P.A., Mitchell, D.J., Pattabiraman, K., Pelkey, E.T., Steinman, L. and Rothbard, J.B. (2000) The design, synthesis and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc. Natl. Acad. Sci. U.S.A. 97, 13003-13008
152. Wiethoff, C.M., Smith, J.G., Koe, G.S. and Middaugh, C.R. (2001) The potential role of proteoglycans in cationic lipid-mediated gene delivery. Studies of the interaction of cationic lipid-DNA complexes with model glycosaminoglycans, J. Biol. Chem. 276, 32806-32813
153. Wimley, W.C. and White, S.H. (1996) Experimentally determined hydrophobicity scale for proteins at membrane interfaces. Nat. Struct. Biol. 3, 842-848
154. Xia, H., Mao, Q., Paulson, H.L. and Davidson, B.L. (2002) siRNA-mediated gene silencing in vitro and in vivo. Nat. Biotechnol. 20, 1006-1010
155. Yoneda, A. and Couchman, J.R. (2003) Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans. Matrix Biol. 1, 25-33
156. Zatsepin, T.S., Turner, J.J., Oretskaya, T.S. and Gait, M.J. (2005) Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing. Curr. Pharm. Des. 11, 3639-3654
157. Zeineddine, D., Papadimou, E., Chebli, K., Gineste, M., Liu, J., Grey, C., Thurig, S., Behfar, A., Wallace, V.A., Skerjanc, I.S. and Puceat, M. (2006) Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. Dev Cell. 11, 535-546
158. Ziegler, A., Nervi, P., Dürrenberger, M. and Seelig, J. (2005) The cationic cell-penetrating peptide CPP(TAT) derived from the HIV-1 protein TAT is rapidly transported into living fibroblasts: optical, biophysical, and metabolic evidence. Biochemistry 44, 138-148