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. 2007 Feb 9;9(1):E18–E29. doi: 10.1208/aapsj0901003

Peptide-guided gene delivery

Molly E Martin 1, Kevin G Rice 1,
PMCID: PMC2751301  PMID: 17408236

Abstract

Although currently less efficient than their viral counter-parts, nonviral vectors are under intense investigation as a safer alternative for gene therapy. For successful delivery, the nonviral vector must be able to overcome many barriers to protect DNA and specifically deliver it for efficient gene expression in target cells. The use of peptides as gene delivery vectors is advantageous over other nonviral agents in that they are able to achieve all of these goals. This review will focus on the application of peptides to mediate nonviral gene delivery. By examining the literature over the past 20 years, it becomes clear that no other class of biomolecules are simultaneously capable of DNA condensation, blocking metabolism, endosomal escape, nuclear localization, and receptor targeting. Based on virtually limitless diversity of peptide sequence and function information from nature, it is increasingly clear that peptide-guided gene delivery is still in its infancy.

Keywords: Peptide-guided gene delivery, fusogenic peptide, nuclear localization, targeted delivery, proteasome

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References

  • 1.Glover DJ, Lipps HJ, Jans DA. Towards safe, nonviral therapeutic gene expression in humans. Nat Rev Genet. 2005;6:299–310. doi: 10.1038/nrg1577. [DOI] [PubMed] [Google Scholar]
  • 2.Schwartz JJ, Zhang S. Peptide-mediated cellular delivery. Curr Opin Mol Ther. 2000;2:162–167. [PubMed] [Google Scholar]
  • 3.Jackson DA, Juranek S, Lipps HJ. Designing nonviral vectors for efficient gene transfer and long-term gene expression. Mol Ther. 2006;14:613–626. doi: 10.1016/j.ymthe.2006.03.026. [DOI] [PubMed] [Google Scholar]
  • 4.Mahato RI. Nonviral peptide-based approaches to gene delivery. J Drug Target. 1999;7:249–268. doi: 10.3109/10611869909085509. [DOI] [PubMed] [Google Scholar]
  • 5.Wadhwa MS, Collard WT, Adami RC, McKenzie DL, Rice KG. Peptide-mediated gene delivery: influence of peptide structure on gene expression. Bioconjug Chem. 1997;8:81–88. doi: 10.1021/bc960079q. [DOI] [PubMed] [Google Scholar]
  • 6.Adami RC, Rice KG. Metabolic stability of glutaraldehyde cross-linked peptide DNA condensates. J Pharm Sci. 1999;88:739–746. doi: 10.1021/js990042p. [DOI] [PubMed] [Google Scholar]
  • 7.McKenzie DL, Kwok KY, Rice KG. A potent new class of reductively activated peptide gene delivery agents. J Biol Chem. 2000;275:9970–9977. doi: 10.1074/jbc.275.14.9970. [DOI] [PubMed] [Google Scholar]
  • 8.Gupta B, Levchenko TS, Torchilin VP. Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides. Adv Drug Deliv Rev. 2005;57:637–651. doi: 10.1016/j.addr.2004.10.007. [DOI] [PubMed] [Google Scholar]
  • 9.Deshayes S, Morris MC, Divita G, Heitz F. Cell-penetrating peptides: tools for intracellular delivery of therapeutics. Cell Mol Life Sci. 2005;62:1839–1849. doi: 10.1007/s00018-005-5109-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Gorlich D, Mattaj IW. Nucleocytoplasmic transport. Science. 1996;271:1513–1518. doi: 10.1126/science.271.5255.1513. [DOI] [PubMed] [Google Scholar]
  • 11.Bremner KH, Seymour LW, Pouton CW. Hamessing nuclear localization pathways for transgene delivery. Curr Opin Mol Ther. 2001;3:170–177. [PubMed] [Google Scholar]
  • 12.El-Aneed A. An overview of current delivery systems in cancer gene therapy. J Control Release. 2004;94:1–14. doi: 10.1016/j.jconrel.2003.09.013. [DOI] [PubMed] [Google Scholar]
  • 13.Tiera MJ, Winnik FO, Fernandes JC. Synthetic and natural polycations for gene therapy: state of the art and new perspectives. Curr Gene Ther. 2006;6:59–71. doi: 10.2174/156652306775515510. [DOI] [PubMed] [Google Scholar]
  • 14.Tang MX, Szoka FC. The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes. Gene Ther. 1997;4:823–832. doi: 10.1038/sj.gt.3300454. [DOI] [PubMed] [Google Scholar]
  • 15.Mannisto M, Vanderkerken S, Toncheva V, et al. Structure-activity relationships of poly(L-lysines): effects of pegylation and molecular shape on physicochemical and biological properties in gene delivery. J Control Release. 2002;83:169–182. doi: 10.1016/S0168-3659(02)00178-5. [DOI] [PubMed] [Google Scholar]
  • 16.Ward CM, Read ML, Seymour LW. Systemic circulation of poly(L-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy. Blood. 2001;97:2221–2229. doi: 10.1182/blood.V97.8.2221. [DOI] [PubMed] [Google Scholar]
  • 17.Gottschalk S, Sparrow JT, Hauer J, et al. A novel DNA-peptide complex for efficient gene transfer and expression in mammalian cells. Gene Ther. 1996;3:448–457. [PubMed] [Google Scholar]
  • 18.Plank C, Tang MX, Wolfe AR, Szoka FC. Branched cationic peptides for gene delivery: role of type and number of cationic residues in formation and in vitro activity of DNA polyplexes. Hum Gene Ther. 1999;10:319–332. doi: 10.1089/10430349950019101. [DOI] [PubMed] [Google Scholar]
  • 19.McKenzie DL, Collard WT, Rice KG. Comparative gene transfer efficiency of low molecular weight polylysine DNA-condensing peptides. J Pept Res. 1999;54:311–318. doi: 10.1034/j.1399-3011.1999.00104.x. [DOI] [PubMed] [Google Scholar]
  • 20.Adami RC, Collard WT, Gupta SA, Kwok KY, Bonadio J, Rice KG. Stability of peptide-condensed Plasmid DNA formulations. J Pharm Sci. 1998;87:678–683. doi: 10.1021/js9800477. [DOI] [PubMed] [Google Scholar]
  • 21.McKenzie D, Smiley B, Kwok KY, Rice KG. Low molecular weight disulfide cross-linking peptides as nonviral gene delivery carriers. Bioconjug Chem. 2000;11:901–911. doi: 10.1021/bc000056i. [DOI] [PubMed] [Google Scholar]
  • 22.Read ML, Singh S, Ahmed Z, et al. A versatile reducible polycationbased system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res. 2005;33:e86–e86. doi: 10.1093/nar/gni085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Pichon C, Goncalves C, Midoux P. Histidine-rich peptides and polymers for nucleic acids delivery. Adv Drug Deliv Rev. 2001;53:75–94. doi: 10.1016/S0169-409X(01)00221-6. [DOI] [PubMed] [Google Scholar]
  • 24.Midoux P, LeCam E, Coulaud D, Delain E, Pichon C. Histidine containing peptides and polypeptides as nucleic acid vectors. Somat Cell Mol Genet. 2002;27:27–47. doi: 10.1023/A:1022931923153. [DOI] [PubMed] [Google Scholar]
  • 25.Midoux P, Kichler A, Boutin V, Maurizot JC, Monsigny M. Membrane permeabilization and efficient gene transfer by a peptide containing several histidines. Bioconjug Chem. 1998;9:260–267. doi: 10.1021/bc9701611. [DOI] [PubMed] [Google Scholar]
  • 26.Mahat RI, Monera OD, Smith LC, Rolland A. Peptide-based gene delivery. Curr Opin Mol Ther. 1999;1:226–243. [PubMed] [Google Scholar]
  • 27.Wagner E, Plank C, Zatloukal K, Cotten M, Birnstiel ML. Influenza virus hemagglutinin HA-2 N-terminal fusogenic peptides augment gene transfer by transferrin-polylysine-DNA complexes: toward a synthetic virus-like gene-transfer vehicle. Proc Natl Acad Sci USA. 1992;89:7934–7938. doi: 10.1073/pnas.89.17.7934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Plank C, Oberhauser B, Mechtler K, Koch C, Wagner E. The influence of endosome-disruptive peptides on gene transfer using synthetic virus-like gene transfer systems. J Biol Chem. 1994;269:12918–12924. [PubMed] [Google Scholar]
  • 29.Ogris M, Carlisle RC, Bettinger T, Seymour LW. Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem. 2001;276:47550–47555. doi: 10.1074/jbc.M108331200. [DOI] [PubMed] [Google Scholar]
  • 30.Boeckle S, Wagner E, Ogris M. C-versus N-terminally linked meltittin-polyethylenimine conjugates: the site of linkage strongly influences activity of DNA polyplexes. J Gene Med. 2005;7:1335–1347. doi: 10.1002/jgm.783. [DOI] [PubMed] [Google Scholar]
  • 31.Boeckle S, Fahrmeir J, Roedl W, Ogris M, Wagner E. Melittin analogs with high lytic activity at endosomal pH enhance transfection with purified targeted PEI polyplexes. J Control Release. 2006;112:240–248. doi: 10.1016/j.jconrel.2006.02.002. [DOI] [PubMed] [Google Scholar]
  • 32.Chen CP, Kim JS, Steenblock E, Liu D, Rice KG. Gene transfer with poly-melittin peptides. Bioconjug Chem. 2006;17:1057–1062. doi: 10.1021/bc060028l. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Fawell S, Seery J, Daikh Y, et al. Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA. 1994;91:664–668. doi: 10.1073/pnas.91.2.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ruben S, Perkins A, Purcell R, et al. Structural and functional characterization of human immunodeficiency virus tat protein. J Virol. 1989;63:1–8. doi: 10.1128/jvi.63.1.1-8.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Vives E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem. 1997;272:16010–16017. doi: 10.1074/jbc.272.25.16010. [DOI] [PubMed] [Google Scholar]
  • 36.Vives E. Cellular uptake [correction of utake] of the Tat peptide: an endocytosis mechanism following ionic interactions. J Mol Recognit. 2003;16:265–271. doi: 10.1002/jmr.636. [DOI] [PubMed] [Google Scholar]
  • 37.Brooks H, Lebleu B, Vives E. Tat peptide-mediated cellular delivery: back to basics. Adv Drug Deliv Rev. 2005;57:559–577. doi: 10.1016/j.addr.2004.12.001. [DOI] [PubMed] [Google Scholar]
  • 38.Rudolph C, Plank C, Lausier J, Schillinger U, Muller RH, Rosenecker J. Oligomers of the arginine-rich motif of the HIV-1 TAT protein are capable of transferring plasmid DNA into cells. J Biol Chem. 2003;278:11411–11418. doi: 10.1074/jbc.M211891200. [DOI] [PubMed] [Google Scholar]
  • 39.Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269:10444–10450. [PubMed] [Google Scholar]
  • 40.Derossi D, Chassaing G, Prochiantz A. Trojan peptides: the penetratin system for intracellular delivery. Trends Cell Biol. 1998;8:84–87. doi: 10.1016/S0962-8924(97)01214-2. [DOI] [PubMed] [Google Scholar]
  • 41.Pooga M, Hallbrink M, Zorko M, Langel U. Cell penetration by transportan. FASEB J. 1998;12:67–77. doi: 10.1096/fasebj.12.1.67. [DOI] [PubMed] [Google Scholar]
  • 42.Pooga M, Kut C, Kihlmark M, et al. Cellular translocation of proteins by transportan. FASEB J. 2001;15:1451–1453. doi: 10.1096/fj.00-0780fje. [DOI] [PubMed] [Google Scholar]
  • 43.Subbarao NK, Parente RA, Szoka FC, Nadasdi L, Pongracz K. pH-Dependent bilayer destabilization by an amphipathic peptide. Biochemistry. 1987;26:2964–2972. doi: 10.1021/bi00385a002. [DOI] [PubMed] [Google Scholar]
  • 44.Parente RA, Nadasdi L, Subbarao NK, Szoka FC. Association of a pH-sensitive peptide with membrane vesicles: role of amino acid sequence. Biochemistry. 1990;29:8713–8719. doi: 10.1021/bi00489a030. [DOI] [PubMed] [Google Scholar]
  • 45.Parente RA, Nir S, Szoka FC. Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA. Biochemistry. 1990;29:8720–8728. doi: 10.1021/bi00489a031. [DOI] [PubMed] [Google Scholar]
  • 46.Wyman TB, Nicol F, Zelphati O, Scaria PV, Plank C, Szoka FC. Design, synthesis and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry. 1997;36:3008–3017. doi: 10.1021/bi9618474. [DOI] [PubMed] [Google Scholar]
  • 47.Rittner K, Benavente A, Bompard-Sorlet A, et al. New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. Mol Ther. 2002;5:104–114. doi: 10.1006/mthe.2002.0523. [DOI] [PubMed] [Google Scholar]
  • 48.Kim J, Chen CP, Rice KG. The proteasome metabolizes peptide-mediated nonviral gene delivery systems. Gene Ther. 2005;12:1581–1590. doi: 10.1038/sj.gt.3302575. [DOI] [PubMed] [Google Scholar]
  • 49.Lanford RE, Kanda P, Kennedy RC. Induction of nuclear transport with a synthetic peptide homologous to the SV40T antigen transport signal. Cell. 1986;46:575–582. doi: 10.1016/0092-8674(86)90883-4. [DOI] [PubMed] [Google Scholar]
  • 50.Collas P, Husebye H, Alestrom P. The nuclear localization sequence of the SV40T antigen promotes transgene uptake and expression in zebrafish embryo nuclei. Transgenic Res. 1996;5:451–458. doi: 10.1007/BF01980210. [DOI] [PubMed] [Google Scholar]
  • 51.Collas P, Alestrom P. Nuclear localization signal of SV40T antigen directs import of plasmid DNA into sea urchin male pronuclei in vitro. Mol Reprod Dev. 1996;45:431–438. doi: 10.1002/(SICI)1098-2795(199612)45:4<431::AID-MRD4>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  • 52.Lanford RE, Butel JS. Construction and characterization of an SV40 mutant defective in nuclear transport of T antigen. Cell. 1984;37:801–813. doi: 10.1016/0092-8674(84)90415-X. [DOI] [PubMed] [Google Scholar]
  • 53.Gharakhanian E, Takahashi J, Kasamatsu H. The carboxyl 35 amino acids of SV40 Vp3 are essential for its nuclear accumulation. Virology. 1987;157:440–448. doi: 10.1016/0042-6822(87)90286-8. [DOI] [PubMed] [Google Scholar]
  • 54.Lyons RH, Ferguson BQ, Rosenberg M. Pentapeptide nuclear localization signal in adenovirus E 1a. Mol Cell Biol. 1987;7:2451–2456. doi: 10.1128/mcb.7.7.2451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Dang CV, Lee WM. Identification of the human c-myc protein nuclear translocation signal. Mol Cell Biol. 1988;8:4048–4054. doi: 10.1128/mcb.8.10.4048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Robbins J, Dilworth SM, Laskey RA, Dingwall C. Two interdependent basic domains in nucleoplasm in nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell. 1991;64:615–623. doi: 10.1016/0092-8674(91)90245-T. [DOI] [PubMed] [Google Scholar]
  • 57.Kleinschmidt JA, Seiter A. Identification of domains involved in nuclear uptake and histone binding of protein N1 of Xenopus laevis. EMBO J. 1988;7:1605–1614. doi: 10.1002/j.1460-2075.1988.tb02986.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Kiefer P, Acland P, Pappin D, Peters G, Dickson C. Competition between nuclear localization and secretory signals determines the subcellular fate of a single CUG-initiated form of FGF3. EMBO J. 1994;13:4126–4136. doi: 10.1002/j.1460-2075.1994.tb06730.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Schreiber V, Molinete M, Boeuf H, de Murcia G, Menissier-de Murcia J. The human poly(ADP-ribose) polymerase nuclear localization signal is a bipartite element functionally separate from DNA binding and catalytic activity. EMBO J. 1992;11:3263–3269. doi: 10.1002/j.1460-2075.1992.tb05404.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Subramanian A, Ranganathan P, Diamond SL. Nuclear targeting peptide scaffolds for lipofection of nondividing mammalian cells. Nat Biotechnol. 1999;17:873–877. doi: 10.1038/70175. [DOI] [PubMed] [Google Scholar]
  • 61.Collins L, Fabre JW. A synthetic peptide vector system for optimal gene delivery to corneal endothelium. J Gene Med. 2004;6:185–194. doi: 10.1002/jgm.482. [DOI] [PubMed] [Google Scholar]
  • 62.Collins L, Gustafsson K, Fabre JW. Tissue-binding properties of a synthetic peptide DNA vector targeted to cell membrane integrins: a possible universal nonviral vector for organ and tissue transplantation. Transplantation. 2000;69:1041–1050. doi: 10.1097/00007890-200003270-00006. [DOI] [PubMed] [Google Scholar]
  • 63.Schneider H, Harbottle RP, Yokosaki Y, Kunde J, Sheppard D, Coutelle C. A novel peptide, PLAEIDGIELTY, for the targeting of alpha9betal-integrins. FEBS Lett. 1998;429:269–273. doi: 10.1016/S0014-5793(98)00612-7. [DOI] [PubMed] [Google Scholar]
  • 64.McKay T, Reynolds P, Jezzard S, Curiel D, Coutelle C. Secretin-mediated gene delivery, a specific targeting mechanism with potential for treatment of biliary and pancreatic disease in cystic fibrosis. Mol Ther. 2002;5:447–454. doi: 10.1006/mthe.2002.0560. [DOI] [PubMed] [Google Scholar]
  • 65.Liu X, Tian PK, Ju DW, et al. Systemic genetic transfer of p21WAF-1 and GM-CSF utilizing of a novel oligopeptide-based EGF receptor targeting polyplex. Cancer Gene Ther. 2003;10:529–539. doi: 10.1038/sj.cgt.7700596. [DOI] [PubMed] [Google Scholar]
  • 66.Zeng J, Too HP, Ma Y, Luo ESE, Wang S. A synthetic peptide containing loop 4 of nerve growth factor for targeted gene delivery. J Gene Med. 2004;6:1247–1256. doi: 10.1002/jgm.610. [DOI] [PubMed] [Google Scholar]
  • 67.Martinez-Fong D, Navarro-Quiroga I, Ochoa I, et al. Neurotensin-SPDP-poly-L-lysine conjugate: a nonviral vector for targeted gene delivery to neural cells. Brain Res Mol Brain Res. 1999;69:249–262. doi: 10.1016/S0169-328X(99)00114-X. [DOI] [PubMed] [Google Scholar]
  • 68.White SJ, Nicklin SA, Sawamura T, Baker AH. Identification of peptides that target the endothelial cell-specific LOX-1 receptor. Hypertension. 2001;37:449–455. doi: 10.1161/01.hyp.37.2.449. [DOI] [PubMed] [Google Scholar]
  • 69.Bloomfield VA. DNA condensation. Curr Opin Struct Biol. 1996;6:334–341. doi: 10.1016/S0959-440X(96)80052-2. [DOI] [PubMed] [Google Scholar]
  • 70.Wu GY, Wu CH. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J Biol Chem. 1987;262:4429–4432. [PubMed] [Google Scholar]
  • 71.Wu GY, Wu CH. Evidence for targeted gene delivery to Hep G2 hepatoma cells in vitro. Biochemistry. 1988;27:887–892. doi: 10.1021/bi00403a008. [DOI] [PubMed] [Google Scholar]
  • 72.Wu GY, Wu CH. Receptor-mediated gene delivery and expression in vivo. J Biol Chem. 1988;263:14621–14624. [PubMed] [Google Scholar]
  • 73.Haines AM, Irvine AS, Mountain A, et al. CL22—a novel cationic peptide for efficient transfection of mammalian cells. Gene Ther. 2001;8:99–110. doi: 10.1038/sj.gt.3301314. [DOI] [PubMed] [Google Scholar]
  • 74.Read ML, Bremner KH, Oupicky D, Green NK, Searle PF, Seymour LW. Vectors based on reducible polycations facilitate intracellular release of nucleic acids. J Gene Med. 2003;5:232–245. doi: 10.1002/jgm.331. [DOI] [PubMed] [Google Scholar]
  • 75.Boussif O, Lezoualc'h F, Zanta MA, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA. 1995;92:7297–7301. doi: 10.1073/pnas.92.16.7297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Thomas M, Klibanov AM. Enhancing polyethylenimine's delivery of plasmid DNA into mammalian cells. Proc Natl Acad Sci USA. 2002;99:14640–14645. doi: 10.1073/pnas.192581499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Kichler A, Leborgne C, Marz J, Danos O, Bechinger B. Histidinerich amphipathic peptide antibiotics promote efficient delivery of DNA into mammalian cells. Proc Natl Acad Sci USA. 2003;100:1564–1568. doi: 10.1073/pnas.0337677100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Midoux P, Monsigny M. Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjug Chem. 1999;10:406–411. doi: 10.1021/bc9801070. [DOI] [PubMed] [Google Scholar]
  • 79.Fajac I, Allo JC, Souil E, et al. Histidylated polylysine as a synthetic vector for gene transfer into immortalized cystic fibrosis airway surface and airway gland serous cells. J Gene Med. 2000;2:368–378. doi: 10.1002/1521-2254(200009/10)2:5<368::AID-JGM118>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  • 80.Bello Roufai M, Midoux P. Histidylated polylysine as DNA vector: elevation of the imidazole protonation and reduced cellular uptake without change in the polyfection efficiency of serum stabilized negative polyplexes. Bioconjug Chem. 2001;12:92–99. doi: 10.1021/bc0000738. [DOI] [PubMed] [Google Scholar]
  • 81.Pichon C, Roufai MB, Monsigny M, Midoux P. Histidylated oligolysines increase the transmembrane passage and the biological activity of antisense oligonucleotides. Nucleic Acids Res. 2000;28:504–512. doi: 10.1093/nar/28.2.504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Cho YW, Kim JD, Park K. Polycation gene delivery systems: escape from endosomes to cytosol. J Pharm Pharmacol. 2003;55:721–734. doi: 10.1211/002235703765951311. [DOI] [PubMed] [Google Scholar]
  • 83.Blondelle SE, Houghten RA. Hemolytic and antimicrobial activities of the twenty-four individual omission analogues of melittin. Biochemistry. 1991;30:4671–4678. doi: 10.1021/bi00233a006. [DOI] [PubMed] [Google Scholar]
  • 84.Groll M, Ditzel L, Lowe J, et al. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. 1997;386:463–471. doi: 10.1038/386463a0. [DOI] [PubMed] [Google Scholar]
  • 85.Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001;8:739–758. doi: 10.1016/S1074-5521(01)00056-4. [DOI] [PubMed] [Google Scholar]
  • 86.Duan D, Yue Y, Yan Z, Yang J, Engelhardt JF. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest. 2000;105:1573–1587. doi: 10.1172/JCI8317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Leonchiks A, Stavropoulou V, Sharipo A, Masucci MG. Inhibition of ubiquitin-dependent proteolysis by a synthetic glycine-alanine repeat peptide that mimics an inhibitory viral sequence. FEBS Lett. 2002;522:93–98. doi: 10.1016/S0014-5793(02)02897-1. [DOI] [PubMed] [Google Scholar]
  • 88.Sharipo A, Imreh M, Leonchiks A, Branden C, Masucci MG. cis-Inhibition of proteasomal degradation by viral repeats: impact of length and amino acid composition. FEBS Lett. 2001;499:137–142. doi: 10.1016/S0014-5793(01)02542-X. [DOI] [PubMed] [Google Scholar]
  • 89.Sharipo A, Imreh M, Leonchiks A, Imreh S, Masucci MG. A minimal glycine-alanine repeat prevents the interaction of ubiquitinated I kappaB alpha with the proteasome: a new mechanism for selective inhibition of proteolysis. Nat Med. 1998;4:939–944. doi: 10.1038/nm0898-939. [DOI] [PubMed] [Google Scholar]
  • 90.Nigg EA. Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature. 1997;386:779–787. doi: 10.1038/386779a0. [DOI] [PubMed] [Google Scholar]
  • 91.Goldfarb DS, Gariepy J, Schoolnik G, Kornberg RD. Synthetic peptides as nuclear localization signals. Nature. 1986;322:641–644. doi: 10.1038/322641a0. [DOI] [PubMed] [Google Scholar]
  • 92.Escriou V, Carriere M, Scherman D, Wils P. NLS bioconjugates for targeting therapeutic genes to the nucleus. Adv Drug Deliv Rev. 2003;55:295–306. doi: 10.1016/S0169-409X(02)00184-9. [DOI] [PubMed] [Google Scholar]
  • 93.Dean DA, Strong DD, Zimmer WE. Nuclear entry of nonviral vectors. Gene Ther. 2005;12:881–890. doi: 10.1038/sj.gt.3302534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Cartier R, Reszka R. Utilization of synthetic peptides containing nuclear localization signals for nonviral gene transfer systems. Gene Ther. 2002;9:157–167. doi: 10.1038/sj.gt.3301635. [DOI] [PubMed] [Google Scholar]
  • 95.Zanta MA, Belguise-Valladier P, Behr JP. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc Natl Acad Sci USA. 1999;96:91–96. doi: 10.1073/pnas.96.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Schatzlein AG. Targeting of synthetic gene delivery systems. J Biomed Biotechnol. 2003;2003:149–158. doi: 10.1155/S1110724303209116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Wolschek MF, Thallinger C, Kursa M, et al. Specific systemic nonviral gene delivery to human hepatocellular carcinoma xenografts in SCID mice. Hepatology. 2002;36:1106–1114. doi: 10.1053/jhep.2002.36372. [DOI] [PubMed] [Google Scholar]
  • 98.Hart SL. Integrin-mediated vectors for gene transfer and therapy. Curr Opin Mol Ther. 1999;1:197–203. [PubMed] [Google Scholar]
  • 99.Hart S, Harbottle R, Cooper R, Miller A, Williamson R, Coutelle C. Gene delivery and expression mediated by an integrin-binding peptide. Gene Ther. 1995;2:552–554. [PubMed] [Google Scholar]
  • 100.Hart SL, Collins L, Gustafsson K, Fabre JW. Integrin-mediated transfection with peptides containing arginine-glycine-aspartic acid domains. Gene Ther. 1997;4:1225–1230. doi: 10.1038/sj.gt.3300513. [DOI] [PubMed] [Google Scholar]

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