Hostname: page-component-cd9895bd7-jn8rn Total loading time: 0 Render date: 2024-12-26T21:27:59.695Z Has data issue: false hasContentIssue false
  • English
  • Français

Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein interactions

Published online by Cambridge University Press:  27 January 2015

John Howl  and
Sarah Jones
John Howl*
Affiliation:
Molecular Pharmacology Group, Research Institute in Healthcare Science, University of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, UK
Sarah Jones
Affiliation:
Molecular Pharmacology Group, Research Institute in Healthcare Science, University of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, UK
*
*Corresponding author: John Howl, Molecular Pharmacology Group, Research Institute in Healthcare Science, University of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, UK. E-mail: J.Howl@wlv.ac.uk
Get access Rights & Permissions [Opens in a new window]

Abstract

Cell-penetrating peptides (CPPs) are reliable vehicles for the target-selective intracellular delivery of therapeutic agents. The identification and application of numerous intrinsically bioactive CPPs, now designated as bioportides, is further endorsement of the tremendous clinical potential of CPP technologies. The refinement of proteomimetic bioportides, particularly sequences that mimic cationic α-helical domains involved in protein-protein interactions (PPIs), provides tremendous opportunities to modulate this emergent drug modality in a clinical setting. Thus, a number of CPP-based constructs are currently undergoing clinical trials as human therapeutics, with a particular focus upon anti-cancer agents. A well-characterised array of synthetic modifications, compatible with modern solid-phase synthesis, can be utilised to improve the biophysical and pharmacological properties of bioportides and so achieve cell-and tissue-selective targeting in vivo. Moreover, considering the recent successful development of stapled α-helical peptides as anti-cancer agents, we hypothesise that similar structural modifications are applicable to the design of bioportides that more effectively modulate the many interactomes known to underlie human diseases. Thus, we propose that stapled-helical bioportides could satisfy all of the clinical requirements for metabolically stable, intrinsically cell-permeable agents capable of regulating discrete PPIs by a dominant negative mode of action with minimal toxicity.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 17 , 2015 , e1
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1 Derossi, D. et al. (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. Journal of Biological Chemistry 269, 10444-10450 Google Scholar
2 Vivès, E., Brodin, P. and Lebleu, B. (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. Journal of Biological Chemistry 272, 16010-16017 Google Scholar
3 Futaki, S. et al. (2001) Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. Journal of Biological Chemistry 276, 5836-5840 CrossRefGoogle ScholarPubMed
4 Jones, S. et al. (2010) Characterization of bioactive cell penetrating peptides from human cytochrome c: protein mimicry and the development of a novel apoptogenic agent. Chemistry & Biology 17, 735-744 Google Scholar
5 Cronican, J. et al. (2011) A class of human proteins that deliver functional proteins into mammalian cells in vitro and in vivo. Chemistry & Biology 18, 833-838 Google Scholar
6 Langel, Ü. (ed.) (2007) Handbook of Cell-Penetrating Peptides, CRC Press, Boca Raton, FL, USA Google Scholar
7 Mae, M. and Langel, Ü. (2006) Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery. Current Opinion in Pharmacology 6, 509-514 Google Scholar
8 Svensen, N., Walton, J.G.A. and Bradley, M. (2012) Peptides for cell-selective drug delivery. Trends in Pharmacological Sciences 33, 186-192 CrossRefGoogle ScholarPubMed
9 Duchard, F. et al. (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8, 849-866 Google Scholar
10 Richard, J.P. et al. (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. Journal of Biological Chemistry 278, 585-590 Google Scholar
11 Rothbard, J.B., Jessop, T.C. and Wender, P.A. (2005) Adaptive translocation: the role of hydrogen bonding and membrane potential in the uptake of guanidinium-rich transporters into cells. Advanced Drug Delivery Reviews 57, 495-504 Google Scholar
12 Meade, B.R. and Dowdy, S.F. (2007) Enhancing the cellular uptake of siRNA duplexes following noncovalent packaging with protein transduction domain peptides. Advanced Drug Delivery Reviews 60, 530-536 CrossRefGoogle ScholarPubMed
13 Räägel, H. et al. (2013) Cell-penetrating peptide secures an efficient endosomal escape of an intact cargo upon a brief photo-induction. Cellular and Molecular Life Sciences 70, 4825-4839 Google Scholar
14 Verdurmen, W.P.R. and Brock, R. (2010) Biological responses towards cationic peptides and drug carriers. Trends in Pharmacological Science 32, 116-124 Google Scholar
15 Howl, J. and Jones, S. (2008) Proteomimetic cell penetrating peptides. International Journal of Peptide Research and Therapeutics 14, 359-366 CrossRefGoogle Scholar
16 Howl, J. et al. (2012) Bioportide: an emergent concept of bioactive cell penetrating peptide. Cellular and Molecular Life Sciences 69, 2951-2966 CrossRefGoogle Scholar
17 Lukanowska, M., Howl, J. and Jones, S. (2013) Bioportides: bioactive cell penetrating peptides that modulate cellular dynamics. Biotechnology Journal 8, 918-930 CrossRefGoogle ScholarPubMed
18 Kiosses, W.B. et al. (2002) A dominant negative p65 PAK peptide inhibits angiogenesis. Circulation Research 90, 697-702 Google Scholar
19 Gangoso, E. et al. (2014) A cell-penetrating peptide based on the interaction between C-src and connexin43 reverses glioma cell phenotype. Cell Death and Disease, 5, e1053 Google Scholar
20 Khavinson, V.Kh. et al. (2013) Mechanism of biological activity of short peptides: cell penetration and epigenetic regulation of gene expression. Biology Bulletins Reviews 3, 451-455 Google Scholar
21 Jones, S. and Thornton, J.M. (1995) Protein-protein interactions: a review of protein dimer structures. Progress in Biophysics and Molecular Biology 63, 31-65 CrossRefGoogle ScholarPubMed
22 Smith, M.C. and Gestwicki, J.E. (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Reviews in Molecular Medicine 14, e16 Google Scholar
23 Ivanov, A.A., Khuri, F.R. and Fu, H. (2013) Targeting protein-protein interactions as an anticancer strategy. Trends in Pharmacological Sciences 34, 393-400 Google Scholar
24 Arkin, M.R. and Wells, J.A. (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nature Reviews in Drug Discovery 3, 301-317 Google Scholar
25 Hopkins, A.L. and Groom, C.R. (2002) The druggable genome. Nature Reviews Drug Discovery 1, 727-730 Google Scholar
26 Thiel, P., Kaiser, M. and Ottmann, C. (2012) Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery? Angewandte Chemie International Edition 51, 2012-2018 CrossRefGoogle ScholarPubMed
27 Rask-Andersen, M., Almén, M.S. and Schiöth, H.B. (2011) Trends in the exploitation of novel drug targets. Nature Reviews Drug Discovery 10, 579-590 Google Scholar
28 Hansen, M., Kilk, K. and Langel, Ü. (2008) Predicting cell-penetrating peptides. Advanced Drug Delivery Reviews 60, 572-579 CrossRefGoogle ScholarPubMed
29 Hällbrink, M. et al. (2005) Prediction of cell-penetrating peptides. International Journal of Peptide Research and Therapeutics 11, 249-259 Google Scholar
30 Jochim, A.L. and Arora, P.S. (2009) Assessment of helical interfaces in protein-protein interactions. Molecular BioSystems 5, 924-926 CrossRefGoogle ScholarPubMed
31 Verdine, G.L. and Hillinski, G.J. (2012) Stapled peptides for intracellular drug targets. Methods in Enzymology 503, 3-33 CrossRefGoogle ScholarPubMed
32 Mullard, A. (2012) Protein-protein interaction inhibitors get into the groove. Nature Reviews Drug Discovery 11, 173-175 Google Scholar
33 Zhao, Y., Bernard, D. and Wang, S. (2013) Small molecule inhibitors of MDM2-p53 and MDMX-p53 interactions as new cancer therapeutics. BioDisovery 8, 1-15 Google Scholar
34 White, A.W., Westwell, A.D. and Brahemi, G. (2008) Protein-protein interactions as targets for small-molecule therapeutics in cancer. Expert Reviews in Molecular Medicine 10, e8 Google Scholar
35 Pooga, M. et al. (1998) Cell penetration by transportan. FASEB Journal 12, 67-77 Google Scholar
36 Soomets, U. et al. (2000) Deletion analogues of transportan. Biochimica et Biophysica Acta 1467, 165-176 Google Scholar
37 Jones, S. et al. (2008) Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis. Biochmica et. Biophyica Acta 1783, 849-863 CrossRefGoogle ScholarPubMed
38 Vasconcelos, L., Pärn, K. and Langel, Ü. (2013) Therapeutic potential of cell-penetrating peptides. Therapeutic Delivery 4, 573-591 Google Scholar
39 Vivès, E., Schmidt, J. and Pèlegrin, A. (2008) Cell-penetrating and cell-targeting peptides in drug delivery. Biochimica et Biophysica Acta 1786, 126-138 Google Scholar
40 Johnson, R.M., Harrison, S.D. and Maclean, D. (2011) Therapeutic applications of cell-penetrating peptides. Methods in Molecular Biology 683, 535-551 CrossRefGoogle ScholarPubMed
41 Tréhin, R. and Merkle, H.P. (2004) Chances and pitfalls of cell penetrating peptides for cellular drug delivery. European Journal of Pharmaceutics and Biopharmaceutics 58, 209-223 Google Scholar
42 Gump, J.M. and Dowdy, S.F. (2007) Tat transduction: the molecular mechanism and therapeutic prospects. Trends in Molecular Medicine 13, 443-448 CrossRefGoogle ScholarPubMed
43 Aina, O.H. et al. (2007) From combinatorial chemistry to cancer-targeting peptides. Molecular Pharmacology 4, 631-651 Google Scholar
44 Rivinoja, A. and Laakkonen, P. (2011) Identification of homing peptides using the in vivo phage display technology. Methods in Molecular Biology 683, 401-415 Google Scholar
45 Nguyen, Q.T. et al. (2010) Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proceedings of the National Academy of Sciences USA 107, 4317-4322 Google Scholar
46 Weinstain, R. et al. (2013) In vivo targeting of hydrogen peroxide by activatable cell-penetrating peptides. Journal of the American Chemical Society 136, 874-877 CrossRefGoogle Scholar
47 Jin, E. et al. (2013) Acid-active cell-penetrating peptides for in vivo tumor-targeted drug delivery. Journal of the American Chemical Society 135, 933-940 Google Scholar
48 Sidhu, S.S. et al. (2000) Phage display for selection of novel binding peptides. Methods in Enzymology, 328, 333-363 Google Scholar
49 Eriste, E. et al. (2013) Peptide-based glioma-targeted drug delivery vector gHope2. Bioconjugate Chemistry 24, 305-313 CrossRefGoogle ScholarPubMed
50 Pollaro, L. and Heinis, C. (2010) Strategies to prolong the plasma residence time of peptide drugs. Medicinal Chemistry Communications 1, 319-324 CrossRefGoogle Scholar
51 Turk, B. (2006) Targeting proteases: successes, failures and future prospects. Nature Reviews Drug Discovery 5, 785-799 Google Scholar
52 Järver, P., Mäger, I. and Langel, Ü. (2010) In vivo biodistribution and efficacy of peptide mediated delivery. Trends in Pharmacological Sciences 31, 528-535 CrossRefGoogle ScholarPubMed
53 Guichard, G. et al. (1994) Antigenic mimicry of natural L-peptides with retro-inverso-peptidomimetics. Proceedings of the National Academy of Sciences USA 91, 9765-9769 Google Scholar
54 Werle, M. and Bernkop-Schnürch, A. (2006) Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 30, 351-367 CrossRefGoogle ScholarPubMed
55 Wender, P.A. et al. (2008) The design of guanidinium-rich transporters and their internalization mechanisms. Advanced Drug Delivery Reviews 60, 452-472 Google Scholar
56 Simon, R.J. et al. (1992) Peptoids: a modular approach to drug discovery. Proceedings of the National Academy of Sciences USA 89, 9367-9371 Google Scholar
57 McGregor, D.P. (2008) Discovering and improving novel peptide therapeutics. Current Opinion in Pharmacology 8, 616-619 CrossRefGoogle ScholarPubMed
58 Holm, T. et al. (2011) Retro-inversion of certain cell-penetrating peptides causes severe cellular toxicity. Biochimica et Biophysica Acta 1808, 1544-1551 Google Scholar
59 Craik, D.J. et al. (2013) The future of peptide-based drugs. Chemical Biology and Drug Design, 81, 136-147 Google Scholar
60 Olmez, E.F. and Akbulut, B.S. (2012) Protein-peptide interactions revolutionize drug development. In Binding Protein (Abdelmohsen, K. ed.), ISBN: 978-953-51-0758-3, InTech, DOI: 10.5772/48418 Google Scholar
61 Schwyzer, R. (1977) ACTH: a short introductory review. Annals of the New York Academy of Sciences 297, 3-26 Google Scholar
62 Johansson, H.J. et al. (2008) Characterization of a novel cytotoxic cell-penetrating peptide derived from p14ARF protein. Molecular Therapy 16, 115-123 Google Scholar
63 Löfgren, K. et al. (2008) Antiprion properties of prion protein-derived cell-penetrating peptides. FASEB Journal 22, 2177-2184 Google Scholar
64 McGuire, M.J. et al. (2014) Identification and characterization of a suite of tumor targeting peptides for non-small cell lung cancer. Science. Report. 4, 4480; doi:10.1038/srep04480 Google Scholar
65 Li, K. et al. (2014) Targeting acute myeloid leukemia with a proapototic peptide conjugated to a toll-like receptor 2-mediated cell-penetrating peptide. International Journal of Cancer 134, 692-702 CrossRefGoogle Scholar
66 Crowley, P.B. and Golovin, A. (2005) Cation-π interactions in protein-protein interfaces. PROTEINS: Structure, Function and Bioinformatics 59, 231-239 Google Scholar
67 Moreira, I.S., Fernandes, P.A. and Ramos, M.J. (2007) Hot spots-A review of the protein-protein interface determinant amino acid residues. Proteins 68, 803-812 Google Scholar
68 Östlund, P. et al. (2005) Cell-penetrating mimics of agonist-activated G-protein coupled receptors. International Journal of Peptide Research and Therapeutics 11, 237-247 Google Scholar
69 Lewis, P.A. and Manzoni, C. (2012) LRRK2 and human disease: a complicated question or a question of complexes? Science Signaling 5, pe2 Google Scholar
70 Holm, P. et al. (2006) Studying the uptake of cell-penetrating peptides. Nature Protocols 1, 1001-1005 Google Scholar
71 Burlina, F. et al. (2005) Quantification of the cellular uptake of cell-penetrating peptides by MALDI-TOF mass spectrometry. Angewandte Chemie International Edition 44, 4244-4247 Google Scholar
72 Jones, S. and Howl, J. (2012) Enantiomer-specific bioactivities of peptidomimetic analogues of mastoparan and mitoparan: characterization of inverso mastoparan as a highly efficient cell penetrating peptide. Bioconjugate Chemistry 23, 47-56 Google Scholar
73 Hällbrink, M. et al. (2004) Uptake of cell-penetrating peptides is dependent on peptide-to-cell ratio rather than on peptide concentration. Biochimica et Biophysica Acta 1667, 222-228 Google Scholar
74 Gomez, J.A. et al. (2010) Cell-penetrating penta-peptides (CPP5 s): measurement of cell entry and protein-transduction activity. Pharmaceuticals 3, 3594-3613 Google Scholar
75 Sagan, S. et al. (2010) Quantification and proteolytic analysis of cell-penetrating peptides and cargo in eukaryote cells. In Membrane Active Peptides: Methods and Results on Structure and Function (Castanho, M.A.R.B., ed.), pp. 247-270, International University Line Publishers, La Jolla, CA, USA Google Scholar
76 Dosil, M. et al. (1998) Dominant-negative mutations in the G-protein-coupled α-factor receptor map to the extracellular ends of the transmembrane segments. Molecular and Cellular Biology 18, 5981-5991 Google Scholar
77 Williams, D.A. et al. (2000) Dominant negative mutation of the hematopoetic-specific Rho-GTPase, Rac2, is associated with human phagocyte immunodeficiency. Blood 96, 1646-1654 Google Scholar
78 Harada, Y. et al. (2010) Cell-permeable peptide DEPDC1-ZNF224 interferes with transcriptional repression and oncogenecity in bladder cancer cells. Cancer Research 70, 5829-5839 CrossRefGoogle Scholar
79 McCusker, C.T. et al. (2007) Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide. Journal of Immunology 179, 2556-2564 Google Scholar
80 Johansson, H.J., El Andaloussi, S. and Langel, Ü. (2011) Mimicry of protein function with cell-penetrating peptides. Methods in Molecular Biology 683, 233-247 Google Scholar
81 Farias, E.F. et al. (2010) Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells. Proceedings of the National Academy of Sciences USA 107, 11811-11816 Google Scholar
82 Smith, L.J. et al. (1996) The concept of a random coil. Residual structure sin peptides and denatures proteins. Current Biology Folding & Design 1, R95-R106 Google Scholar
83 Deshayes, S. et al. (2007) Interactions of cell-penetrating peptides with model membranes. In Handbook of Cell-Penetrating Peptides (Langel, Ü., ed.), pp. 139-160, CRC Press, Boca Raton, FL, USA Google Scholar
84 Schwyzer, R. (1992) Conformations and orientations of amphiphilic peptides induced by artificial lipid membranes: correlations with biological activity. Chemtracts: Biochemistry and Molecular Biology 3, 347-379 Google Scholar
85 Ladokhin, A.S. and White, S.H. (1999) Folding of amphipathic α-helices on membranes: energetics of helix formation by melittin. Journal of Molecular Biology 285, 1363-1369 Google Scholar
86 Jones, S. and Howl, J. (2009) Mastoparans. In Bioactive Peptides (Howl, J. and Jones, S., eds), pp. 429-445, CRC Press, Boca Raton, FL, USA Google Scholar
87 Bechara, C. et al. (2013) Trytophan within basic peptide sequences triggers glycosaminoglycan-dependent endocytosis. FASEB Journal, 27, 738-749 CrossRefGoogle Scholar
88 Esbjörner, E.K., Gräslund, A. and Nordén, B. (2007) Membrane interactions of cell-penetrating peptides. In Handbook of Cell-Penetrating Peptides (Langel, Ü., ed.), pp. 109-137, CRC Press, Boca Raton, FL, USA Google Scholar
89 Grubbs, R.H. (2004) Olefin metathesis. Tetrahedron 60, 7117-7140 Google Scholar
90 Kim, Y.-W., Kutchuklan, P.S. and Verdine, G.L. (2010) Introduction of all-hydrocarbon i,i+3 staples into α-helices via ring-closing olefin metathesis. Organic Letters 12, 3046-3049 Google Scholar
91 Kim, Y.-W. and Verdine, G.L. (2009) Stereochemical effects of all-hydrocarbon tethers in i.i+4 stapled peptides. Bioorganic and Medicinal Chemistry Letters 19, 2533-2536 Google Scholar
92 Kim, Y-W., Grossmann, T.N. and Verdine, G.L. (2011) Synthesis of all-hydrocarbon stapled α-helical peptides by ring-closing olefin metathesis. Nature Protocols 6, 761-771 Google Scholar
93 Le Guezennec, X., Vriend, G. and Stunnenberg, H.G. (2004) Molecular determinants of the interaction of Mad with the PAH2 domain of mSin3. Journal of Biological Chemistry 279, 25823-25829 Google Scholar
94 Ponting, C.P. and Russell, R.R. (2002) The natural history of protein domains. Annual Review of Biophysics and Biomolecular Structure 31, 45-71 Google Scholar
95 Basu, M.K. et al. (2008) Evolution of protein domain promiscuity in eukaryotes. Genome Research 18, 449-461 Google Scholar
96 Pawson, T. and Nash, P. (2000) Protein-protein interactions define specificity in signal transduction. Genes & Development 14, 1027-1047 Google Scholar
97 Wilson, A.J. (2009) Inhibition of protein-protein interactions using designed molecules. Chemical Society Reviews 38, 3289-3300 Google Scholar
98 Verdine, G.L. and Hilinski, G.J. (2012) All-hydrocarbon stapled peptides as synthetic cell-accessible mini-proteins. Drug Discovery Today: Technologies 9, e41-e47 Google Scholar
99 Bedford, M.T. and Richard, S. (2005) Arginine methylation: an emerging regulator of protein function. Molecular Cell 18, 263-272 Google Scholar
100 Boisvert, F.M., Chénard, C.A. and Richard, S. (2005) Protein interfaces in signaling regulated by arginine methylation. Science Signaling 15, re2 Google Scholar
101 Jones, S. and Thornton, J.M. (1996) Principles of protein-protein interactions. Proceedings of the National Academy of Sciences USA 93, 13-20 Google Scholar
102 Henchey, L.K., Jochim, A.L. and Arora, P.S. (2008) Contemporary strategies for the stabilization of peptides in the α-helical conformation. Current Opinion in Chemical Biology 12, 692-697 Google Scholar
103 Walensky, L.D. et al. (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305, 1466-1470 Google Scholar
104 Moellering, R.E. et al. (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182-188 Google Scholar
105 Chang, Y.S. et al. (2013) Stapled αhelical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dpenedent cancer therapy. Proceedings of the National Academy of Sciences USA 110, E3445-E3454 Google Scholar
106 Cheok, C.F. et al. (2011) Translating p53 into the clinic. Nature Reviews Clinical Oncology 8, 25-37 Google Scholar
107 Warso, M.A. et al. (2013) A first-in-class, first-in-human, phase 1 trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquination in patients with advanced solid tumours. British Journal of Cancer 108, 1061-1071 Google Scholar
108 Lipinski, C.A. (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies 1, 337-341 Google Scholar
109 Vidal, M., Cusick, M.E. and Barabási, A-L. (2011) Interactome networks and human disease. Cell 144, 986-998 Google Scholar
110 Gentilucci, L., De Marco, R. and Cerisoli, L. (2013) Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Current Pharmaceutical Design 16, 3185-3203 Google Scholar