Skip to main content
SpringerLink
Log in
Book cover

Site-Specific Protein Labeling pp 29–53Cite as

Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1266))

Abstract

The ability to efficiently access cytosolic proteins is desired in both biological research and medicine. However, targeting intracellular proteins is often challenging, because to reach the cytosol, exogenous molecules must first traverse the cell membrane. This review provides a broad overview of how certain molecules are thought to cross this barrier, and what kinds of approaches are being made to enhance the intracellular delivery of those that are impermeable. We first discuss rules that govern the passive permeability of small molecules across the lipid membrane, and mechanisms of membrane transport that have evolved in nature for certain metabolites, peptides, and proteins. Then, we introduce design strategies that have emerged in the development of small molecules and peptides with improved permeability. Finally, intracellular delivery systems that have been engineered for protein payloads are surveyed. Viewpoints from varying disciplines have been brought together to provide a cohesive overview of how the membrane barrier is being overcome.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Stein WD, Lieb WR (1986) Transport and diffusion across cell membranes, 1st edn. Academic, Orlando, FL

    Google Scholar 

  2. Alberts B, Johnson A, Lewis J et al (2007) Molecular biology of the cell, 5th edn. Garland Science, New York

    Google Scholar 

  3. Di L, Artursson P, Avdeef A et al (2012) Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov Today 17:905–912. doi:10.1016/j.drudis.2012.03.015

    CAS  PubMed  Google Scholar 

  4. Engelman DM (2005) Membranes are more mosaic than fluid. Nature 438:578–580. doi:10.1038/nature04394

    CAS  PubMed  Google Scholar 

  5. Jacobson K, Mouritsen OG, Anderson RGW (2007) Lipid rafts: at a crossroad between cell biology and physics. Nat Cell Biol 9:7–14. doi:10.1038/ncb0107-7

    CAS  PubMed  Google Scholar 

  6. Koichi K, Michiya F, Makoto N (1974) Lipid components of two different regions of an intestinal epithelial cell membrane of mouse. Biochim Biophys Acta 369:222–233. doi:10.1016/0005-2760(74)90253-7

    Google Scholar 

  7. Marsh D, Horváth LI (1998) Structure, dynamics and composition of the lipid-protein interface. Perspectives from spin-labelling. Biochim Biophys Acta 1376:267–296. doi:10.1016/S0304-4157(98)00009-4

    CAS  PubMed  Google Scholar 

  8. Lee AG (2003) Lipid–protein interactions in biological membranes: a structural perspective. Biochim Biophys Acta 1612:1–40. doi:10.1016/S0005-2736(03)00056-7

    CAS  PubMed  Google Scholar 

  9. Zachowski A (1993) Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J 294:1–14

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Leventis R, Silvius JR (2001) Use of cyclodextrins to monitor transbilayer movement and differential lipid affinities of cholesterol. Biophys J 81:2257–2267. doi:10.1016/S0006-3495(01)75873-0

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Steck TL, Ye J, Lange Y (2002) Probing red cell membrane cholesterol movement with cyclodextrin. Biophys J 83:2118–2125. doi:10.1016/S0006-3495(02)73972-6

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44. doi:10.1038/nature01451

    CAS  PubMed  Google Scholar 

  13. Mercer J, Helenius A (2009) Virus entry by macropinocytosis. Nat Cell Biol 11:510–520. doi:10.1038/ncb0509-510

    CAS  PubMed  Google Scholar 

  14. Alberts B, Johnson A, Lewis J et al (2002) Molecular biology of the cell. http://www.ncbi.nlm.nih.gov/books/NBK21054/. Accessed 27 Feb 2014

  15. Orsi M, Essex JW (2010) Passive permeation across lipid bilayers: a literature review. In: Molecular simulations and biomembranes: from biophysics to function, p 76–90

    Google Scholar 

  16. Kansy M, Senner F, Gubernator K (1998) Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem 41:1007–1010. doi:10.1021/jm970530e

    CAS  PubMed  Google Scholar 

  17. Sugano K, Kansy M, Artursson P et al (2010) Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov 9:597–614. doi:10.1038/nrd3187

    CAS  PubMed  Google Scholar 

  18. Di L, Whitney-Pickett C, Umland JP et al (2011) Development of a new permeability assay using low-efflux MDCKII cells. J Pharm Sci 100:4974–4985. doi:10.1002/jps.22674

    CAS  PubMed  Google Scholar 

  19. Shamu CE, Story CM, Rapoport TA, Ploegh HL (1999) The pathway of Us11-dependent degradation of Mhc class I heavy chains involves a ubiquitin-conjugated intermediate. J Cell Biol 147:45–58. doi:10.1083/jcb.147.1.45

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Bartz R, Fan H, Zhang J et al (2011) Effective siRNA delivery and target mRNA degradation using an amphipathic peptide to facilitate pH-dependent endosomal escape. Biochem J 435:475–487. doi:10.1042/BJ20101021

    CAS  PubMed  Google Scholar 

  21. Bittner MA, Holz RW (1988) Effects of tetanus toxin on catecholamine release from intact and digitonin-permeabilized chromaffin cells. J Neurochem 51:451–456. doi:10.1111/j.1471-4159.1988.tb01059.x

    CAS  PubMed  Google Scholar 

  22. Moellering RE, Cornejo M, Davis TN et al (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462:182–188. doi:10.1038/nature08543

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Chang YS, Graves B, Guerlavais V et al (2013) Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci 110:E3445–E3454. doi:10.1073/pnas.1303002110

  24. Bonner DK, Leung C, Chen-Liang J et al (2011) Intracellular trafficking of polyamidoamine-poly(ethylene glycol) block copolymers in DNA delivery. Bioconjug Chem 22:1519–1525. doi:10.1021/bc200059v

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Richard JP, Melikov K, Vives E et al (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem 278:585–590. doi:10.1074/jbc.M209548200

    CAS  PubMed  Google Scholar 

  26. Bechara C, Sagan S (2013) Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett 587:1693–1702. doi:10.1016/j.febslet.2013.04.031

    CAS  PubMed  Google Scholar 

  27. Cebrian I, Visentin G, Blanchard N et al (2011) Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell 147:1355–1368. doi:10.1016/j.cell.2011.11.021

    CAS  PubMed  Google Scholar 

  28. Yu P, Liu B, Kodadek T (2005) A high-throughput assay for assessing the cell permeability of combinatorial libraries. Nat Biotechnol 23:746–751. doi:10.1038/nbt1099

    CAS  PubMed  Google Scholar 

  29. Holub JM, LaRochelle JR, Appelbaum JS, Schepartz A (2013) Improved assays for determining the cytosolic access of peptides, proteins, and their mimetics. Biochemistry (Mosc) 52:9036–9046. doi:10.1021/bi401069g

    CAS  Google Scholar 

  30. Zlokarnik G, Negulescu PA, Knapp TE et al (1998) Quantitation of transcription and clonal selection of single living cells with β-lactamase as reporter. Science 279:84–88. doi:10.1126/science.279.5347.84

  31. Bordonaro M (2009) Modular Cre/lox system and genetic therapeutics for colorectal cancer. J Biomed Biotechnol. doi:10.1155/2009/358230

    PubMed Central  PubMed  Google Scholar 

  32. Yamaizumi M, Mekada E, Uchida T, Okada Y (1978) One molecule of diphtheria toxin fragment a introduced into a cell can kill the cell. Cell 15:245–250. doi:10.1016/0092-8674(78)90099-5

    CAS  PubMed  Google Scholar 

  33. Eiklid K, Olsnes S, Pihl A (1980) Entry of lethal doses of abrin, ricin and modeccin into the cytosol of HeLa cells. Exp Cell Res 126:321–326. doi:10.1016/0014-4827(80)90270-0

    CAS  PubMed  Google Scholar 

  34. Diamond JM, Katz Y (1974) Interpretation of nonelectrolyte partition coefficients between dimyristoyl lecithin and water. J Membr Biol 17:121–154. doi:10.1007/BF01870176

    CAS  PubMed  Google Scholar 

  35. Finkelstein A (1976) Water and nonelectrolyte permeability of lipid bilayer membranes. J Gen Physiol 68:127–135. doi:10.1085/jgp.68.2.127

    CAS  PubMed  Google Scholar 

  36. Subczynski WK, Hyde JS, Kusumi A (1989) Oxygen permeability of phosphatidylcholine–cholesterol membranes. Proc Natl Acad Sci 86:4474–4478

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Gutknecht J, Bisson MA, Tosteson FC (1977) Diffusion of carbon dioxide through lipid bilayer membranes: effects of carbonic anhydrase, bicarbonate, and unstirred layers. J Gen Physiol 69:779–794. doi:10.1085/jgp.69.6.779

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Walter A, Gutknecht J (1986) Permeability of small nonelectrolytes through lipid bilayer membranes. J Membr Biol 90:207–217. doi:10.1007/BF01870127

    CAS  PubMed  Google Scholar 

  39. Orbach E, Finkelstein A (1980) The nonelectrolyte permeability of planar lipid bilayer membranes. J Gen Physiol 75:427–436. doi:10.1085/jgp.75.4.427

    CAS  PubMed  Google Scholar 

  40. Papahadjopoulos D, Nir S, Oki S (1972) Permeability properties of phospholipid membranes: effect of cholesterol and temperature. Biochim Biophys Acta 266:561–583

    CAS  PubMed  Google Scholar 

  41. Mendel CM (1989) The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10:232–274. doi:10.1210/edrv-10-3-232

    CAS  PubMed  Google Scholar 

  42. Giorgi EP, Stein WD (1981) The transport of steroids into animal cells in culture. Endocrinology 108:688–697. doi:10.1210/endo-108-2-688

    CAS  PubMed  Google Scholar 

  43. Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13:821–836

    CAS  PubMed  Google Scholar 

  44. Augustijns PF, Bradshaw TP, Gan LSL et al (1993) Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporine A transport. Biochem Biophys Res Commun 197:360–365. doi:10.1006/bbrc.1993.2487

    CAS  PubMed  Google Scholar 

  45. Rezai T, Bock JE, Zhou MV et al (2006) Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J Am Chem Soc 128:14073–14080. doi:10.1021/ja063076p

    CAS  PubMed  Google Scholar 

  46. Guimarães CRW, Mathiowetz AM, Shalaeva M et al (2012) Use of 3D properties to characterize beyond rule-of-5 property space for passive permeation. J Chem Inf Model 52:882–890. doi:10.1021/ci300010y

    PubMed  Google Scholar 

  47. Hediger MA, Clémençon B, Burrier RE, Bruford EA (2013) The ABCs of membrane transporters in health and disease (SLC series): introduction. Mol Aspects Med 34:95–107. doi:10.1016/j.mam.2012.12.009

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Saier MH, Reddy VS, Tamang DG, Vastermark A (2013) The transporter classification database. Nucleic Acids Res 42:D251–D258. doi:10.1093/nar/gkt1097

    PubMed Central  PubMed  Google Scholar 

  49. Hediger MA (2013) The ABCs of membrane transporters in health and disease (SLC series). Mol Aspects Med 34(2–3):95–752

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Kew JNC, Davies CH (2010) Ion channels: from structure to function. Oxford University Press, Oxford

    Google Scholar 

  51. Enyedi P, Czirják G (2010) Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev 90:559–605. doi:10.1152/physrev.00029.2009

    CAS  PubMed  Google Scholar 

  52. Toyoshima C, Kanai R, Cornelius F (2011) First crystal structures of Na+, K + -ATPase: new light on the oldest ion pump. Structure 19:1732–1738. doi:10.1016/j.str.2011.10.016

    CAS  PubMed  Google Scholar 

  53. Duax WL, Griffin JF, Langs DA et al (1996) Molecular structure and mechanisms of action of cyclic and linear ion transport antibiotics. Pept Sci 40:141–155. doi:10.1002/(SICI)1097-0282(1996)40:1<141::AID-BIP6>3.0.CO;2-W

    CAS  Google Scholar 

  54. Wallace BA (1998) Recent advances in the high resolution structures of bacterial channels: gramicidin A. J Struct Biol 121:123–141. doi:10.1006/jsbi.1997.3948

    CAS  PubMed  Google Scholar 

  55. Zheng L, Kostrewa D, Bernèche S et al (2004) The mechanism of ammonia transport based on the crystal structure of AmtB of Escherichia coli. Proc Natl Acad Sci U S A 101:17090–17095. doi:10.1073/pnas.0406475101

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Andrade SLA, Einsle O (2007) The Amt/Mep/Rh family of ammonium transport proteins. Mol Membr Biol 24:357–365. doi:10.1080/09687680701388423

    CAS  PubMed  Google Scholar 

  57. Shayakul C, Clémençon B, Hediger MA (2013) The urea transporter family (SLC14): physiological, pathological and structural aspects. Mol Aspects Med 34:313–322. doi:10.1016/j.mam.2012.12.003

    CAS  PubMed  Google Scholar 

  58. Ishibashi K, Hara S, Kondo S (2009) Aquaporin water channels in mammals. Clin Exp Nephrol 13:107–117. doi:10.1007/s10157-008-0118-6

    CAS  PubMed  Google Scholar 

  59. Bienert GP, Chaumont F (2013) Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide. Biochim Biophys Acta. doi:10.1016/j.bbagen.2013.09.017

    Google Scholar 

  60. Mueckler M, Thorens B (2013) The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 34:121–138. doi:10.1016/j.mam.2012.07.001

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Schweikhard ES, Ziegler CM (2012) Amino acid secondary transporters: toward a common transport mechanism. Curr Top Membr 70:1–28. doi:10.1016/B978-0-12-394316-3.00001-6

    CAS  PubMed  Google Scholar 

  62. Young JD, Yao SYM, Baldwin JM et al (2013) The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol Aspects Med 34:529–547. doi:10.1016/j.mam.2012.05.007

    CAS  PubMed  Google Scholar 

  63. Smith DE, Clémençon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34:323–336. doi:10.1016/j.mam.2012.11.003

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Letschert K, Faulstich H, Keller D, Keppler D (2006) Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci 91:140–149. doi:10.1093/toxsci/kfj141

    CAS  PubMed  Google Scholar 

  65. Chen Z-S, Tiwari AK (2011) Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J 278:3226–3245. doi:10.1111/j.1742-4658.2011.08235.x

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7:27–34. doi:10.4137/DTI.S12519

    PubMed Central  PubMed  Google Scholar 

  67. Natarajan K, Xie Y, Baer MR, Ross DD (2012) Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol 83:1084–1103. doi:10.1016/j.bcp.2012.01.002

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Langel U (2010) Handbook of cell-penetrating peptides, 2nd edn. CRC Press, Boca Raton

    Google Scholar 

  69. Sagan S, Burlina F, Alves ID et al (2013) Homeoproteins and homeoprotein-derived peptides: going in and out. Curr Pharm Des 19:2851–2862

    CAS  PubMed  Google Scholar 

  70. Schmidt N, Mishra A, Lai GH, Wong GCL (2010) Arginine-rich cell-penetrating peptides. FEBS Lett 584:1806–1813. doi:10.1016/j.febslet.2009.11.046

    CAS  PubMed  Google Scholar 

  71. Futaki S, Hirose H, Nakase I (2013) Arginine-rich peptides: methods of translocation through biological membranes. Curr Pharm Des 19:2863–2868

    CAS  PubMed  Google Scholar 

  72. Tyagi M, Rusnati M, Presta M, Giacca M (2001) Internalization of HIV-1 Tat requires cell surface heparan sulfate proteoglycans. J Biol Chem 276:3254–3261. doi:10.1074/jbc.M006701200

    CAS  PubMed  Google Scholar 

  73. Su Y, Waring AJ, Ruchala P, Hong M (2010) Membrane-bound dynamic structure of an arginine-rich cell-penetrating peptide, the protein transduction domain of HIV TAT, from solid-state NMR. Biochemistry (Mosc) 49:6009–6020. doi:10.1021/bi100642n

    CAS  Google Scholar 

  74. Wadia JS, Stan RV, Dowdy SF (2004) Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med 10:310–315. doi:10.1038/nm996

    CAS  PubMed  Google Scholar 

  75. Nakase I, Tadokoro A, Kawabata N et al (2007) Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry (Mosc) 46:492–501. doi:10.1021/bi0612824

    CAS  Google Scholar 

  76. Yesylevskyy S, Marrink S-J, Mark AE (2009) Alternative mechanisms for the interaction of the cell-penetrating peptides penetratin and the TAT peptide with lipid bilayers. Biophys J 97:40–49. doi:10.1016/j.bpj.2009.03.059

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Herce HD, Garcia AE, Litt J et al (2009) Arginine-rich peptides destabilize the plasma membrane, consistent with a pore formation translocation mechanism of cell-penetrating peptides. Biophys J 97:1917–1925. doi:10.1016/j.bpj.2009.05.066

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Mishra A, Lai GH, Schmidt NW et al (2011) Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions. Proc Natl Acad Sci 108:16883–16888. doi:10.1073/pnas.1108795108

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Kawamoto S, Miyakawa T, Takasu M et al (2012) Cell-penetrating peptide induces various deformations of lipid bilayer membrane: inverted micelle, double bilayer, and transmembrane. Int J Quantum Chem 112:178–183. doi:10.1002/qua.23177

    CAS  Google Scholar 

  80. Huang K, García AE (2013) Free energy of translocating an arginine-rich cell-penetrating peptide across a lipid bilayer suggests pore formation. Biophys J 104:412–420. doi:10.1016/j.bpj.2012.10.027

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Jones S, Howl J (2012) Enantiomer-specific bioactivities of peptidomimetic analogues of mastoparan and mitoparan: characterization of inverso mastoparan as a highly efficient cell penetrating peptide. Bioconjug Chem 23:47–56. doi:10.1021/bc2002924

    CAS  PubMed  Google Scholar 

  82. Tréhin R, Krauss U, Beck-Sickinger AG et al (2004) Cellular uptake but low permeation of human calcitonin-derived cell penetrating peptides and Tat(47-57) through well-differentiated epithelial models. Pharm Res 21:1248–1256. doi:10.1023/B:PHAM.0000033013.45204.c3

    PubMed  Google Scholar 

  83. Foerg C, Merkle HP (2008) On the biomedical promise of cell penetrating peptides: limits versus prospects. J Pharm Sci 97:144–162. doi:10.1002/jps.21117

    CAS  PubMed  Google Scholar 

  84. Sandvig K, van Deurs B (2005) Delivery into cells: lessons learned from plant and bacterial toxins. Gene Ther 12:865–872. doi:10.1038/sj.gt.3302525

    CAS  PubMed  Google Scholar 

  85. Falnes PØ, Sandvig K (2000) Penetration of protein toxins into cells. Curr Opin Cell Biol 12:407–413. doi:10.1016/S0955-0674(00)00109-5

    CAS  PubMed  Google Scholar 

  86. Collier RJ (2009) Membrane translocation by anthrax toxin. Mol Aspects Med 30:413–422. doi:10.1016/j.mam.2009.06.003

    CAS  PubMed Central  PubMed  Google Scholar 

  87. De Virgilio M, Lombardi A, Caliandro R, Fabbrini MS (2010) Ribosome-inactivating proteins: from plant defense to tumor attack. Toxins 2:2699–2737. doi:10.3390/toxins2112699

    PubMed Central  PubMed  Google Scholar 

  88. Spooner RA, Lord JM (2012) How ricin and shiga toxin reach the cytosol of target cells: retrotranslocation from the endoplasmic reticulum. In: Mantis N (ed) Ricin shiga toxins. Springer, Berlin, pp 19–40

    Google Scholar 

  89. Sandvig K, Skotland T, van Deurs B, Klokk TI (2013) Retrograde transport of protein toxins through the Golgi apparatus. Histochem Cell Biol 140:317–326. doi:10.1007/s00418-013-1111-z

    CAS  PubMed  Google Scholar 

  90. Wernick NLB, Chinnapen DJ-F, Cho JA, Lencer WI (2010) Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins 2:310–325. doi:10.3390/toxins2030310

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Cho JA, Chinnapen DJ-F, Aamar E et al (2012) Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins. Front Cell Infect Microbiol. doi:10.3389/fcimb.2012.00051

    Google Scholar 

  92. Mercer J, Schelhaas M, Helenius A (2010) Virus entry by endocytosis. Annu Rev Biochem 79:803–833. doi:10.1146/annurev-biochem-060208-104626

    CAS  PubMed  Google Scholar 

  93. Sriwilaijaroen N, Suzuki Y (2012) Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proc Jpn Acad Ser B Phys Biol Sci 88:226–249. doi:10.2183/pjab.88.226

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Tsai B (2007) Penetration of nonenveloped viruses into the cytoplasm. Annu Rev Cell Dev Biol 23:23–43. doi:10.1146/annurev.cellbio.23.090506.123454

    CAS  PubMed  Google Scholar 

  95. Johnson J, Banerjee M (2008) Activation, exposure and penetration of virally encoded, membrane-active polypeptides during non-enveloped virus entry. Curr Protein Pept Sci 9:16–27. doi:10.2174/138920308783565732

    PubMed  Google Scholar 

  96. Moyer CL, Nemerow GR (2011) Viral weapons of membrane destruction: variable modes of membrane penetration by non-enveloped viruses. Curr Opin Virol 1:44–99. doi:10.1016/j.coviro.2011.05.002

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Inoue T, Tsai B (2013) How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb Perspect Biol 5:a013250. doi:10.1101/cshperspect.a013250

    PubMed  Google Scholar 

  98. Suomalainen M, Greber UF (2013) Uncoating of non-enveloped viruses. Curr Opin Virol 3:27–33. doi:10.1016/j.coviro.2012.12.004

    CAS  PubMed  Google Scholar 

  99. Veber DF, Johnson SR, Cheng H-Y et al (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623. doi:10.1021/jm020017n

    CAS  PubMed  Google Scholar 

  100. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25. doi:10.1016/S0169-409X(96)00423-1

    CAS  Google Scholar 

  101. Faller B, Ottaviani G, Ertl P et al (2011) Evolution of the physicochemical properties of marketed drugs: can history foretell the future? Drug Discov Today 16:976–984. doi:10.1016/j.drudis.2011.07.003

    CAS  PubMed  Google Scholar 

  102. Ertl P, Rohde B, Selzer P (2000) Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem 43:3714–3717. doi:10.1021/jm000942e

    CAS  PubMed  Google Scholar 

  103. Xiang T-X, Anderson BD (1998) Influence of chain ordering on the selectivity of dipalmitoylphosphatidylcholine bilayer membranes for permeant size and shape. Biophys J 75:2658–2671. doi:10.1016/S0006-3495(98)77711-2

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Kuhn B, Mohr P, Stahl M (2010) Intramolecular hydrogen bonding in medicinal chemistry. J Med Chem 53:2601–2611. doi:10.1021/jm100087s

    CAS  PubMed  Google Scholar 

  105. Mayer PT, Xiang T-X, Anderson BD (2000) Independence of substituent contributions to the transport of small-molecule permeants in lipid bilayer. AAPS Pharm Sci 2:40–52. doi:10.1208/ps020214

    Google Scholar 

  106. Ulander J, Haymet ADJ (2003) Permeation across hydrated DPPC lipid bilayers: simulation of the titrable amphiphilic drug valproic acid. Biophys J 85:3475–3484. doi:10.1016/S0006-3495(03)74768-7

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Xiang T-X, Anderson BD (2006) Liposomal drug transport: a molecular perspective from molecular dynamics simulations in lipid bilayers. Adv Drug Deliv Rev 58:1357–1378. doi:10.1016/j.addr.2006.09.002

    CAS  PubMed  Google Scholar 

  108. Bennett WFD, MacCallum JL, Hinner MJ et al (2009) Molecular view of cholesterol flip-flop and chemical potential in different membrane environments. J Am Chem Soc 131:12714–12720. doi:10.1021/ja903529f

    CAS  PubMed  Google Scholar 

  109. Maeda K, Sugiyama Y (2013) Transporter biology in drug approval: regulatory aspects. Mol Aspects Med 34:711–718. doi:10.1016/j.mam.2012.10.012

    CAS  PubMed  Google Scholar 

  110. Dobson PD, Patel Y, Kell DB (2009) “Metabolite-likeness” as a criterion in the design and selection of pharmaceutical drug libraries. Drug Discov Today 14:31–40. doi:10.1016/j.drudis.2008.10.011

    CAS  PubMed  Google Scholar 

  111. Dahan A, Khamis M, Agbaria R, Karaman R (2012) Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach. Expert Opin Drug Deliv 9:1001–1013. doi:10.1517/17425247.2012.697055

    CAS  PubMed  Google Scholar 

  112. Majumdar S, Duvvuri S, Mitra AK (2004) Membrane transporter/receptor-targeted prodrug design: strategies for human and veterinary drug development. Adv Drug Deliv Rev 56:1437–1452. doi:10.1016/j.addr.2004.02.006

    CAS  PubMed  Google Scholar 

  113. Keppler A, Arrivoli C, Sironi L, Ellenberg J (2006) Fluorophores for live cell imaging of AGT fusion proteins across the visible spectrum. Biotechniques 41:167–170, 172, 174–175

    CAS  PubMed  Google Scholar 

  114. Tsien RY (1981) A non-disruptive technique for loading calcium buffers and indicators into cells. Nature 290:527–528

    CAS  PubMed  Google Scholar 

  115. Ries RS, Choi H, Blunck R et al (2004) Black lipid membranes: visualizing the structure, dynamics, and substrate dependence of membranes. J Phys Chem B 108:16040–16049. doi:10.1021/jp048098h

    CAS  Google Scholar 

  116. Melikyan GB, Deriy BN, Ok DC, Cohen FS (1996) Voltage-dependent translocation of R18 and DiI across lipid bilayers leads to fluorescence changes. Biophys J 71:2680–2691. doi:10.1016/S0006-3495(96)79459-6

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Kleinfeld AM, Chu P, Storch J (1997) Flip-flop is slow and rate limiting for the movement of long chain anthroyloxy fatty acids across lipid vesicles. Biochemistry (Mosc) 36:5702–5711. doi:10.1021/bi962007s

    CAS  Google Scholar 

  118. Homolya L, Holló Z, Germann UA et al (1993) Fluorescent cellular indicators are extruded by the multidrug resistance protein. J Biol Chem 268:21493–21496

    CAS  PubMed  Google Scholar 

  119. Chidley C, Haruki H, Pedersen MG et al (2011) A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. Nat Chem Biol 7:375–383. doi:10.1038/nchembio.557

    CAS  PubMed  Google Scholar 

  120. Driggers EM, Hale SP, Lee J, Terrett NK (2008) The exploration of macrocycles for drug discovery—an underexploited structural class. Nat Rev Drug Discov 7:608–624. doi:10.1038/nrd2590

    CAS  PubMed  Google Scholar 

  121. Giordanetto F, Revell JD, Knerr L et al (2013) Stapled vasoactive intestinal peptide (VIP) derivatives improve VPAC2 agonism and glucose-dependent insulin secretion. ACS Med Chem Lett 4:1163–1168. doi:10.1021/ml400257h

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Bock JE, Gavenonis J, Kritzer JA (2013) Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints. ACS Chem Biol 8:488–499. doi:10.1021/cb300515u

    CAS  PubMed  Google Scholar 

  123. Kwon Y-U, Kodadek T (2007) Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem Biol 14:671–677. doi:10.1016/j.chembiol.2007.05.006

    CAS  PubMed  Google Scholar 

  124. White TR, Renzelman CM, Rand AC et al (2011) On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol 7:810–817. doi:10.1038/nchembio.664

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Malakoutikhah M, Prades R, Teixidó M, Giralt E (2010) N-methyl phenylalanine-rich peptides as highly versatile blood−brain barrier shuttles. J Med Chem 53:2354–2363. doi:10.1021/jm901654x

    CAS  PubMed  Google Scholar 

  126. Ovadia O, Greenberg S, Chatterjee J et al (2011) The effect of multiple N-methylation on intestinal permeability of cyclic hexapeptides. Mol Pharm 8:479–487. doi:10.1021/mp1003306

    CAS  PubMed  Google Scholar 

  127. Azzarito V, Long K, Murphy NS, Wilson AJ (2013) Inhibition of α-helix-mediated protein–protein interactions using designed molecules. Nat Chem 5:161–173. doi:10.1038/nchem.1568

  128. Kim Y-W, Grossmann TN, Verdine GL (2011) Synthesis of all-hydrocarbon stapled α-helical peptides by ring-closing olefin metathesis. Nat Protoc 6:761–771. doi:10.1038/nprot.2011.324

  129. Patgiri A, Menzenski MZ, Mahon AB, Arora PS (2010) Solid-phase synthesis of short α-helices stabilized by the hydrogen bond surrogate approach. Nat Protoc 5:1857–1865. doi:10.1038/nprot.2010.146

  130. Miller SE, Kallenbach NR, Arora PS (2012) Reversible alpha-helix formation controlled by a hydrogen bond surrogate. Tetrahedron 68:4434–4437. doi:10.1016/j.tet.2011.12.068

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Patgiri A, Yadav KK, Arora PS, Bar-Sagi D (2011) An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol 7:585–587. doi:10.1038/nchembio.612

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Okamoto T, Zobel K, Fedorova A et al (2013) Stabilizing the pro-apoptotic BimBH3 Helix (BimSAHB) does not necessarily enhance affinity or biological activity. ACS Chem Biol 8:297–302. doi:10.1021/cb3005403

    CAS  PubMed  Google Scholar 

  133. Bird GH, Gavathiotis E, LaBelle JL et al (2014) Distinct BimBH3 (BimSAHB) stapled peptides for structural and cellular studies. ACS Chem Biol 9:831–837. doi:10.1021/cb4003305

    CAS  PubMed  Google Scholar 

  134. Okamoto T, Segal D, Zobel K et al (2014) Further insights into the effects of pre-organizing the BimBH3 helix. ACS Chem Biol 9:838–839. doi:10.1021/cb400638p

    CAS  PubMed  Google Scholar 

  135. Verdine GL, Hilinski GJ (2012) Stapled peptides for intracellular drug targets. In: Dane Wittrup K, Verdine GL (eds) Methods enzymol. Academic, New York, pp 3–33

    Google Scholar 

  136. Bird GH, Christian Crannell W, Walensky LD (2011) Chemical synthesis of hydrocarbon-stapled peptides for protein interaction research and therapeutic targeting. Curr Protoc Chem Biol 3(3):99–117

    PubMed  Google Scholar 

  137. Milletti F (2012) Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today 17:850–860. doi:10.1016/j.drudis.2012.03.002

    CAS  PubMed  Google Scholar 

  138. Copolovici DM, Langel K, Eriste E, Langel U (2014) Cell-penetrating peptides: design synthesis and applications. ACS Nano. doi:10.1021/nn4057269

    PubMed  Google Scholar 

  139. Appelbaum JS, LaRochelle JR, Smith BA et al (2012) Arginine topology controls escape of minimally cationic proteins from early endosomes to the cytoplasm. Chem Biol 19:819–830. doi:10.1016/j.chembiol.2012.05.022

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Marschall ALJ, Frenzel A, Schirrmann T et al (2011) Targeting antibodies to the cytoplasm. mAbs 3:3–16. doi:10.4161/mabs.3.1.14110

    PubMed Central  PubMed  Google Scholar 

  141. Gu Z, Biswas A, Zhao M, Tang Y (2011) Tailoring nanocarriers for intracellular protein delivery. Chem Soc Rev 40:3638–3655. doi:10.1039/C0CS00227E

    CAS  PubMed  Google Scholar 

  142. Du J, Jin J, Yan M, Lu Y (2012) Synthetic nanocarriers for intracellular protein delivery. Curr Drug Metab 13:82–92. doi:10.2174/138920012798356862

    CAS  PubMed  Google Scholar 

  143. Salmaso S, Caliceti P (2013) Self assembling nanocomposites for protein delivery: supramolecular interactions of soluble polymers with protein drugs. Int J Pharm 440:111–123. doi:10.1016/j.ijpharm.2011.12.029

    CAS  PubMed  Google Scholar 

  144. Zhang Y, Yu L-C (2008) Microinjection as a tool of mechanical delivery. Curr Opin Biotechnol 19:506–510. doi:10.1016/j.copbio.2008.07.005

    CAS  PubMed  Google Scholar 

  145. Sharei A, Zoldan J, Adamo A et al (2013) A vector-free microfluidic platform for intracellular delivery. Proc Natl Acad Sci 110:2082–2087. doi:10.1073/pnas.1218705110

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Shalek AK, Robinson JT, Karp ES et al (2010) Vertical silicon nanowires as a universal platform for delivering biomolecules into living cells. Proc Natl Acad Sci 107:1870–1875. doi:10.1073/pnas.0909350107

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Yosef N, Shalek AK, Gaublomme JT et al (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496:461–468. doi:10.1038/nature11981

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Lo SL, Wang S (2010) Peptide-based nanocarriers for intracellular delivery of biologically active proteins. In: Organelle-specific pharmaceutical nanotechnology, p 323–336

    Google Scholar 

  149. Koren E, Torchilin VP (2012) Cell-penetrating peptides: breaking through to the other side. Trends Mol Med 18:385–393. doi:10.1016/j.molmed.2012.04.012

    CAS  PubMed  Google Scholar 

  150. Nakase I, Tanaka G, Futaki S (2013) Cell-penetrating peptides (CPPs) as a vector for the delivery of siRNAs into cells. Mol Biosyst 9:855–861. doi:10.1039/C2MB25467K

    CAS  PubMed  Google Scholar 

  151. Fawell S, Seery J, Daikh Y et al (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci 91:664–668. doi:10.1073/pnas.91.2.664

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Nagahara H, Vocero-Akbani AM, Snyder EL et al (1998) Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med 4:1449–1452. doi:10.1038/4042

    CAS  PubMed  Google Scholar 

  153. Morris MC, Depollier J, Mery J et al (2001) A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat Biotechnol 19:1173–1176. doi:10.1038/nbt1201-1173

    CAS  PubMed  Google Scholar 

  154. Harford-Wright E, Lewis KM, Vink R, Ghabriel MN (2014) Evaluating the role of substance P in the growth of brain tumors. Neuroscience 261:85–94. doi:10.1016/j.neuroscience.2013.12.027

    CAS  PubMed  Google Scholar 

  155. Rizk SS, Luchniak A, Uysal S et al (2009) An engineered substance P variant for receptor-mediated delivery of synthetic antibodies into tumor cells. Proc Natl Acad Sci 106:11011–11015. doi:10.1073/pnas.0904907106

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Rizk SS, Misiura A, Paduch M, Kossiakoff AA (2011) Substance P derivatives as versatile tools for specific delivery of various types of biomolecular cargo. Bioconjug Chem 23:42–46. doi:10.1021/bc200496e

    PubMed Central  PubMed  Google Scholar 

  157. Chatterjee S, Chaudhury S, McShan AC et al (2013) Structure and biophysics of type III secretion in bacteria. Biochemistry (Mosc) 52:2508–2517. doi:10.1021/bi400160a

    CAS  Google Scholar 

  158. Carleton HA, Lara-Tejero M, Liu X, Galán JE (2013) Engineering the type III secretion system in non-replicating bacterial minicells for antigen delivery. Nat Commun 4:1590. doi:10.1038/ncomms2594

    PubMed Central  PubMed  Google Scholar 

  159. Doerner JF, Febvay S, Clapham DE (2012) Controlled delivery of bioactive molecules into live cells using the bacterial mechanosensitive channel MscL. Nat Commun 3:990. doi:10.1038/ncomms1999

    PubMed Central  PubMed  Google Scholar 

  160. Dunstone MA, Tweten RK (2012) Packing a punch: the mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins. Curr Opin Struct Biol 22:342–349. doi:10.1016/j.sbi.2012.04.008

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Provoda CJ, Stier EM, Lee K-D (2003) Tumor cell killing enabled by listeriolysin O-liposome-mediated delivery of the protein toxin gelonin. J Biol Chem 278:35102–35108. doi:10.1074/jbc.M305411200

    CAS  PubMed  Google Scholar 

  162. Pirie CM, Liu DV, Wittrup KD (2013) Targeted cytolysins synergistically potentiate cytoplasmic delivery of gelonin immunotoxin. Mol Cancer Ther 12:1774–1782. doi:10.1158/1535-7163.MCT-12-1023

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Sandvig K, van Deurs B (2002) Membrane traffic exploited by protein toxins. Annu Rev Cell Dev Biol 18:1–24. doi:10.1146/annurev.cellbio.18.011502.142107

    CAS  PubMed  Google Scholar 

  164. Johannes L, Römer W (2010) Shiga toxins—from cell biology to biomedical applications. Nat Rev Microbiol 8:105–116. doi:10.1038/nrmicro2279

    CAS  PubMed  Google Scholar 

  165. Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237. doi:10.1146/annurev.med.58.070605.115320

    CAS  PubMed  Google Scholar 

  166. FitzGerald DJ, Wayne AS, Kreitman RJ, Pastan I (2011) Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Cancer Res 71:6300–6309. doi:10.1158/0008-5472.CAN-11-1374

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Lawrence MS, Phillips KJ, Liu DR (2007) Supercharging proteins can impart unusual resilience. J Am Chem Soc 129:10110–10112. doi:10.1021/ja071641y

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Cronican JJ, Thompson DB, Beier KT et al (2010) Potent delivery of functional proteins into mammalian cells in vitro and in vivo using a supercharged protein. ACS Chem Biol 5:747–752. doi:10.1021/cb1001153

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Cronican JJ, Beier KT, Davis TN et al (2011) A class of human proteins that deliver functional proteins into mammalian cells in vitro and in vivo. Chem Biol 18:833–838. doi:10.1016/j.chembiol.2011.07.003

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Weisbart RH, Noritake DT, Wong AL et al (1990) A conserved anti-DNA antibody idiotype associated with nephritis in murine and human systemic lupus erythematosus. J Immunol 144:2653–2658

    CAS  PubMed  Google Scholar 

  171. Hansen JE, Chan G, Liu Y et al (2012) Targeting cancer with a lupus autoantibody. Sci Transl Med 4:157ra142. doi:10.1126/scitranslmed.3004385

    PubMed Central  PubMed  Google Scholar 

  172. Lawlor MW, Armstrong D, Viola MG et al (2013) Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet 22:1525–1538. doi:10.1093/hmg/ddt003

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Kaczmarczyk SJ, Sitaraman K, Young HA et al (2011) Protein delivery using engineered virus-like particles. Proc Natl Acad Sci 108:16998–17003. doi:10.1073/pnas.1101874108

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Tao P, Mahalingam M, Marasa BS et al (2013) In vitro and in vivo delivery of genes and proteins using the bacteriophage T4 DNA packaging machine. Proc Natl Acad Sci 110:5846–5851. doi:10.1073/pnas.1300867110

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Mallery DL, McEwan WA, Bidgood SR et al (2010) Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci 107:19985–19990. doi:10.1073/pnas.1014074107

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Torchilin V (2008) Intracellular delivery of protein and peptide therapeutics. Drug Discov Today Technol 5:e95–e103. doi:10.1016/j.ddtec.2009.01.002

    PubMed  Google Scholar 

  177. Zelphati O, Wang Y, Kitada S et al (2001) Intracellular delivery of proteins with a new lipid-mediated delivery system. J Biol Chem 276:35103–35110. doi:10.1074/jbc.M104920200

    CAS  PubMed  Google Scholar 

  178. Benjaminsen RV, Mattebjerg MA, Henriksen JR et al (2013) The possible “proton sponge” effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol Ther 21:149–157. doi:10.1038/mt.2012.185

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Behr J-P (1997) The proton sponge: a trick to enter cells the viruses did not exploit. Chim Int J Chem 51:34–36

    CAS  Google Scholar 

  180. Lynn DM, Langer R (2000) Degradable poly(β-amino esters): synthesis, characterization, and self-assembly with plasmid DNA. J Am Chem Soc 122:10761–10768. doi:10.1021/ja0015388

  181. Su X, Yang N, Wittrup KD, Irvine DJ (2013) Synergistic antitumor activity from two-stage delivery of targeted toxins and endosome-disrupting nanoparticles. Biomacromolecules 14:1093–1102. doi:10.1021/bm3019906

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Gu Z, Yan M, Hu B et al (2009) Protein nanocapsule weaved with enzymatically degradable polymeric network. Nano Lett 9:4533–4538. doi:10.1021/nl902935b

    CAS  PubMed  Google Scholar 

  183. Yan M, Du J, Gu Z et al (2010) A novel intracellular protein delivery platform based on single-protein nanocapsules. Nat Nanotechnol 5:48–53. doi:10.1038/nnano.2009.341

    CAS  PubMed  Google Scholar 

  184. Biswas A, Joo K-I, Liu J et al (2011) Endoprotease-mediated intracellular protein delivery using nanocapsules. ACS Nano 5:1385–1394. doi:10.1021/nn1031005

    CAS  PubMed  Google Scholar 

  185. Malmsten M (2013) Inorganic nanomaterials as delivery systems for proteins, peptides, DNA, and siRNA. Curr Opin Colloid Interface Sci 18:468–480. doi:10.1016/j.cocis.2013.06.002

    CAS  Google Scholar 

  186. Loosli H-R, Kessler H, Oschkinat H et al (1985) Peptide conformations. Part 31. The conformation of cyclosporin a in the crystal and in solution. Helv Chim Acta 68:682–704. doi:10.1002/hlca.19850680319

    CAS  Google Scholar 

  187. Bayer P, Kraft M, Ejchart A et al (1995) Structural studies of HIV-1 tat protein. J Mol Biol 247:529–535. doi:10.1016/S0022-2836(05)80133-0

    CAS  PubMed  Google Scholar 

  188. Feld GK, Thoren KL, Kintzer AF et al (2010) Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers. Nat Struct Mol Biol 17:1383–1390. doi:10.1038/nsmb.1923

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Varghese Gupta S, Gupta D, Sun J et al (2011) Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach. Mol Pharm 8:2358–2367. doi:10.1021/mp200291x

    Google Scholar 

Download references

Acknowledgements

The authors thank Bradley Pentelute, Alessandro Angelini, Sandrine Sagan, Alexander H. de Vries, and Christopher Chidley for helpful discussions and critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA

    Nicole J. Yang

  2. Sensitive Farbstoffe GbR, Eugen-Papst-Strasse 9, Munich, 81247, Germany

    Marlon J. Hinner

Authors
  1. Nicole J. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlon J. Hinner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Nicole J. Yang or Marlon J. Hinner .

Editor information

Editors and Affiliations

  1. Department of Chemistry, École Normale Supérieure, Paris, France

    Arnaud Gautier

  2. Sensitive Farbstoffe GbR, Munich, Germany

    Marlon J. Hinner

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this protocol

Cite this protocol

Yang, N.J., Hinner, M.J. (2015). Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins. In: Gautier, A., Hinner, M. (eds) Site-Specific Protein Labeling. Methods in Molecular Biology, vol 1266. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2272-7_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-2272-7_3

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2271-0

  • Online ISBN: 978-1-4939-2272-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation