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

  • Nicole J. YangEmail author
  • Marlon J. HinnerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1266)


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.

Key words

Cell membrane Permeability Translocation Intracellular delivery Cytosolic delivery Fluorescent probe Passive diffusion Membrane transporter, Endosomal escape 



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.


  1. 1.
    Stein WD, Lieb WR (1986) Transport and diffusion across cell membranes, 1st edn. Academic, Orlando, FLGoogle Scholar
  2. 2.
    Alberts B, Johnson A, Lewis J et al (2007) Molecular biology of the cell, 5th edn. Garland Science, New YorkGoogle Scholar
  3. 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 PubMedGoogle Scholar
  4. 4.
    Engelman DM (2005) Membranes are more mosaic than fluid. Nature 438:578–580. doi: 10.1038/nature04394 PubMedGoogle Scholar
  5. 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 PubMedGoogle Scholar
  6. 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. 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 PubMedGoogle Scholar
  8. 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 PubMedGoogle Scholar
  9. 9.
    Zachowski A (1993) Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J 294:1–14PubMedCentralPubMedGoogle Scholar
  10. 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 PubMedCentralPubMedGoogle Scholar
  11. 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 PubMedCentralPubMedGoogle Scholar
  12. 12.
    Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44. doi: 10.1038/nature01451 PubMedGoogle Scholar
  13. 13.
    Mercer J, Helenius A (2009) Virus entry by macropinocytosis. Nat Cell Biol 11:510–520. doi: 10.1038/ncb0509-510 PubMedGoogle Scholar
  14. 14.
    Alberts B, Johnson A, Lewis J et al (2002) Molecular biology of the cell. Accessed 27 Feb 2014
  15. 15.
    Orsi M, Essex JW (2010) Passive permeation across lipid bilayers: a literature review. In: Molecular simulations and biomembranes: from biophysics to function, p 76–90Google Scholar
  16. 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 PubMedGoogle Scholar
  17. 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 PubMedGoogle Scholar
  18. 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 PubMedGoogle Scholar
  19. 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 PubMedCentralPubMedGoogle Scholar
  20. 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 PubMedGoogle Scholar
  21. 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 PubMedGoogle Scholar
  22. 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 PubMedCentralPubMedGoogle Scholar
  23. 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. 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 PubMedCentralPubMedGoogle Scholar
  25. 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 PubMedGoogle Scholar
  26. 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 PubMedGoogle Scholar
  27. 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 PubMedGoogle Scholar
  28. 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 PubMedGoogle Scholar
  29. 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 Google Scholar
  30. 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. 31.
    Bordonaro M (2009) Modular Cre/lox system and genetic therapeutics for colorectal cancer. J Biomed Biotechnol. doi: 10.1155/2009/358230 PubMedCentralPubMedGoogle Scholar
  32. 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 PubMedGoogle Scholar
  33. 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 PubMedGoogle Scholar
  34. 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 PubMedGoogle Scholar
  35. 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 PubMedGoogle Scholar
  36. 36.
    Subczynski WK, Hyde JS, Kusumi A (1989) Oxygen permeability of phosphatidylcholine–cholesterol membranes. Proc Natl Acad Sci 86:4474–4478PubMedCentralPubMedGoogle Scholar
  37. 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 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Walter A, Gutknecht J (1986) Permeability of small nonelectrolytes through lipid bilayer membranes. J Membr Biol 90:207–217. doi: 10.1007/BF01870127 PubMedGoogle Scholar
  39. 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 PubMedGoogle Scholar
  40. 40.
    Papahadjopoulos D, Nir S, Oki S (1972) Permeability properties of phospholipid membranes: effect of cholesterol and temperature. Biochim Biophys Acta 266:561–583PubMedGoogle Scholar
  41. 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 PubMedGoogle Scholar
  42. 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 PubMedGoogle Scholar
  43. 43.
    Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13:821–836PubMedGoogle Scholar
  44. 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 PubMedGoogle Scholar
  45. 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 PubMedGoogle Scholar
  46. 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 PubMedGoogle Scholar
  47. 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 PubMedCentralPubMedGoogle Scholar
  48. 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 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Hediger MA (2013) The ABCs of membrane transporters in health and disease (SLC series). Mol Aspects Med 34(2–3):95–752PubMedCentralPubMedGoogle Scholar
  50. 50.
    Kew JNC, Davies CH (2010) Ion channels: from structure to function. Oxford University Press, OxfordGoogle Scholar
  51. 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 PubMedGoogle Scholar
  52. 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 PubMedGoogle Scholar
  53. 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-WGoogle Scholar
  54. 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 PubMedGoogle Scholar
  55. 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 PubMedCentralPubMedGoogle Scholar
  56. 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 PubMedGoogle Scholar
  57. 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 PubMedGoogle Scholar
  58. 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 PubMedGoogle Scholar
  59. 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. 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 PubMedCentralPubMedGoogle Scholar
  61. 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 PubMedGoogle Scholar
  62. 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 PubMedGoogle Scholar
  63. 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 PubMedCentralPubMedGoogle Scholar
  64. 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 PubMedGoogle Scholar
  65. 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 PubMedCentralPubMedGoogle Scholar
  66. 66.
    Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7:27–34. doi: 10.4137/DTI.S12519 PubMedCentralPubMedGoogle Scholar
  67. 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 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Langel U (2010) Handbook of cell-penetrating peptides, 2nd edn. CRC Press, Boca RatonGoogle Scholar
  69. 69.
    Sagan S, Burlina F, Alves ID et al (2013) Homeoproteins and homeoprotein-derived peptides: going in and out. Curr Pharm Des 19:2851–2862PubMedGoogle Scholar
  70. 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 PubMedGoogle Scholar
  71. 71.
    Futaki S, Hirose H, Nakase I (2013) Arginine-rich peptides: methods of translocation through biological membranes. Curr Pharm Des 19:2863–2868PubMedGoogle Scholar
  72. 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 PubMedGoogle Scholar
  73. 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 Google Scholar
  74. 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 PubMedGoogle Scholar
  75. 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 Google Scholar
  76. 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 PubMedCentralPubMedGoogle Scholar
  77. 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 PubMedCentralPubMedGoogle Scholar
  78. 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 PubMedCentralPubMedGoogle Scholar
  79. 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 Google Scholar
  80. 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 PubMedCentralPubMedGoogle Scholar
  81. 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 PubMedGoogle Scholar
  82. 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 PubMedGoogle Scholar
  83. 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 PubMedGoogle Scholar
  84. 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/ PubMedGoogle Scholar
  85. 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 PubMedGoogle Scholar
  86. 86.
    Collier RJ (2009) Membrane translocation by anthrax toxin. Mol Aspects Med 30:413–422. doi: 10.1016/j.mam.2009.06.003 PubMedCentralPubMedGoogle Scholar
  87. 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 PubMedCentralPubMedGoogle Scholar
  88. 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 19–40Google Scholar
  89. 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 PubMedGoogle Scholar
  90. 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 PubMedCentralPubMedGoogle Scholar
  91. 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. 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 PubMedGoogle Scholar
  93. 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 PubMedCentralPubMedGoogle Scholar
  94. 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 PubMedGoogle Scholar
  95. 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 PubMedGoogle Scholar
  96. 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 PubMedCentralPubMedGoogle Scholar
  97. 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 PubMedGoogle Scholar
  98. 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 PubMedGoogle Scholar
  99. 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 PubMedGoogle Scholar
  100. 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 Google Scholar
  101. 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 PubMedGoogle Scholar
  102. 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 PubMedGoogle Scholar
  103. 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 PubMedCentralPubMedGoogle Scholar
  104. 104.
    Kuhn B, Mohr P, Stahl M (2010) Intramolecular hydrogen bonding in medicinal chemistry. J Med Chem 53:2601–2611. doi: 10.1021/jm100087s PubMedGoogle Scholar
  105. 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. 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 PubMedCentralPubMedGoogle Scholar
  107. 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 PubMedGoogle Scholar
  108. 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 PubMedGoogle Scholar
  109. 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 PubMedGoogle Scholar
  110. 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 PubMedGoogle Scholar
  111. 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 PubMedGoogle Scholar
  112. 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 PubMedGoogle Scholar
  113. 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, 174–175PubMedGoogle Scholar
  114. 114.
    Tsien RY (1981) A non-disruptive technique for loading calcium buffers and indicators into cells. Nature 290:527–528PubMedGoogle Scholar
  115. 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 Google Scholar
  116. 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 PubMedCentralPubMedGoogle Scholar
  117. 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 Google Scholar
  118. 118.
    Homolya L, Holló Z, Germann UA et al (1993) Fluorescent cellular indicators are extruded by the multidrug resistance protein. J Biol Chem 268:21493–21496PubMedGoogle Scholar
  119. 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 PubMedGoogle Scholar
  120. 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 PubMedGoogle Scholar
  121. 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 PubMedCentralPubMedGoogle Scholar
  122. 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 PubMedGoogle Scholar
  123. 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 PubMedGoogle Scholar
  124. 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 PubMedCentralPubMedGoogle Scholar
  125. 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 PubMedGoogle Scholar
  126. 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 PubMedGoogle Scholar
  127. 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. 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. 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. 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 PubMedCentralPubMedGoogle Scholar
  131. 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 PubMedCentralPubMedGoogle Scholar
  132. 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 PubMedGoogle Scholar
  133. 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 PubMedGoogle Scholar
  134. 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 PubMedGoogle Scholar
  135. 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 3–33Google Scholar
  136. 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):99–117PubMedGoogle Scholar
  137. 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 PubMedGoogle Scholar
  138. 138.
    Copolovici DM, Langel K, Eriste E, Langel U (2014) Cell-penetrating peptides: design synthesis and applications. ACS Nano. doi: 10.1021/nn4057269 PubMedGoogle Scholar
  139. 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 PubMedCentralPubMedGoogle Scholar
  140. 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 PubMedCentralPubMedGoogle Scholar
  141. 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 PubMedGoogle Scholar
  142. 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 PubMedGoogle Scholar
  143. 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 PubMedGoogle Scholar
  144. 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 PubMedGoogle Scholar
  145. 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 PubMedCentralPubMedGoogle Scholar
  146. 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 PubMedCentralPubMedGoogle Scholar
  147. 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 PubMedCentralPubMedGoogle Scholar
  148. 148.
    Lo SL, Wang S (2010) Peptide-based nanocarriers for intracellular delivery of biologically active proteins. In: Organelle-specific pharmaceutical nanotechnology, p 323–336Google Scholar
  149. 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 PubMedGoogle Scholar
  150. 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 PubMedGoogle Scholar
  151. 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 PubMedCentralPubMedGoogle Scholar
  152. 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 PubMedGoogle Scholar
  153. 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 PubMedGoogle Scholar
  154. 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 PubMedGoogle Scholar
  155. 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 PubMedCentralPubMedGoogle Scholar
  156. 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 PubMedCentralPubMedGoogle Scholar
  157. 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 Google Scholar
  158. 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 PubMedCentralPubMedGoogle Scholar
  159. 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 PubMedCentralPubMedGoogle Scholar
  160. 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/ PubMedCentralPubMedGoogle Scholar
  161. 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 PubMedGoogle Scholar
  162. 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 PubMedCentralPubMedGoogle Scholar
  163. 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 PubMedGoogle Scholar
  164. 164.
    Johannes L, Römer W (2010) Shiga toxins—from cell biology to biomedical applications. Nat Rev Microbiol 8:105–116. doi: 10.1038/nrmicro2279 PubMedGoogle Scholar
  165. 165.
    Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237. doi: 10.1146/ PubMedGoogle Scholar
  166. 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 PubMedCentralPubMedGoogle Scholar
  167. 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 PubMedCentralPubMedGoogle Scholar
  168. 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 PubMedCentralPubMedGoogle Scholar
  169. 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 PubMedCentralPubMedGoogle Scholar
  170. 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 144:2653–2658PubMedGoogle Scholar
  171. 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 PubMedCentralPubMedGoogle Scholar
  172. 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 PubMedCentralPubMedGoogle Scholar
  173. 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 PubMedCentralPubMedGoogle Scholar
  174. 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 PubMedCentralPubMedGoogle Scholar
  175. 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 PubMedCentralPubMedGoogle Scholar
  176. 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 PubMedGoogle Scholar
  177. 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 PubMedGoogle Scholar
  178. 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 PubMedCentralPubMedGoogle Scholar
  179. 179.
    Behr J-P (1997) The proton sponge: a trick to enter cells the viruses did not exploit. Chim Int J Chem 51:34–36Google Scholar
  180. 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. 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 PubMedCentralPubMedGoogle Scholar
  182. 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 PubMedGoogle Scholar
  183. 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 PubMedGoogle Scholar
  184. 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 PubMedGoogle Scholar
  185. 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 Google Scholar
  186. 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 Google Scholar
  187. 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 PubMedGoogle Scholar
  188. 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 PubMedCentralPubMedGoogle Scholar
  189. 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

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Chemical EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  2. 2.Sensitive Farbstoffe GbRMunichGermany

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