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Designing macrocyclic disulfide-rich peptides for biotechnological applications

Abstract

Bioactive peptides have potential as drug leads, but turning them into drugs is a challenge because of their typically poor metabolic stability. Molecular grafting is one approach to stabilizing and constraining peptides and involves melding a bioactive peptide sequence onto a suitable molecular scaffold. This method has the benefit of improving the stability of the bioactive peptide lead and potentially expanding its functionality. Here we step through the molecular grafting process and describe its successes and limitations. So far, molecular grafting has been successfully used to improve the stability of peptide drug leads, to enhance conformational rigidity, to facilitate delivery to intracellular targets, and in some cases to increase efficacy in oral administration. Although applications of molecular grafting have focused mainly on therapeutic applications, including those for pain, metabolic disease, and cancer, its potential uses are much broader, and we hope this Perspective will inspire wider applications of this molecular design tool in biotechnology.

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Fig. 1: Selected cyclic disulfide-rich peptide scaffolds and their sequence diversity.
Fig. 2: Molecular grafting of epitopes onto scaffolds.
Fig. 3: Applications of molecular grafting.
Fig. 4: The molecular grafting process in rational drug design.
Fig. 5: Design of multivalent peptides by molecular grafting.
Fig. 6: A combinatorial library approach to molecular grafting.

References

  1. 1.

    Craik, D. J., Fairlie, D. P., Liras, S. & Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des. 81, 136–147 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Tsomaia, N. Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem. 94, 459–470 (2015).

    CAS  Article  Google Scholar 

  3. 3.

    Rutledge, S. E., Volkman, H. M. & Schepartz, A. Molecular recognition of protein surfaces: high affinity ligands for the CBP KIX domain. J. Am. Chem. Soc. 125, 14336–14347 (2003).

    CAS  Article  Google Scholar 

  4. 4.

    Sia, S. K. & Kim, P. S. Protein grafting of an HIV-1-inhibiting epitope. Proc. Natl Acad. Sci. USA 100, 9756–9761 (2003).

    CAS  Article  Google Scholar 

  5. 5.

    Ewert, S., Honegger, A. & Plückthun, A. Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering. Methods 34, 184–199 (2004).

    CAS  Article  Google Scholar 

  6. 6.

    Brown, C. J. et al. Rational design and biophysical characterization of thioredoxin-based aptamers: insights into peptide grafting. J. Mol. Biol. 395, 871–883 (2010).

    CAS  Article  Google Scholar 

  7. 7.

    Azoitei, M. L. et al. Computational design of high-affinity epitope scaffolds by backbone grafting of a linear epitope. J. Mol. Biol. 415, 175–192 (2012).

    CAS  Article  Google Scholar 

  8. 8.

    Julian, M. C. et al. Co-evolution of affinity and stability of grafted amyloid-motif domain antibodies. Protein Eng. Des. Sel. 28, 339–350 (2015).

    CAS  Article  Google Scholar 

  9. 9.

    Plückthun, A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu. Rev. Pharmacol. Toxicol. 55, 489–511 (2015).

    Article  Google Scholar 

  10. 10.

    Walker, S. N., Tennyson, R. L., Chapman, A. M., Kennan, A. J. & McNaughton, B. R. GLUE that sticks to HIV: a helix-grafted GLUE protein that selectively binds the HIV gp41 N-terminal helical region. ChemBioChem 16, 219–222 (2015).

    CAS  Article  Google Scholar 

  11. 11.

    Mylne, J. S. et al. Albumins and their processing machinery are hijacked for cyclic peptides in sunflower. Nat. Chem. Biol. 7, 257–259 (2011).

    CAS  Article  Google Scholar 

  12. 12.

    Lehrer, R. I., Cole, A. M. & Selsted, M. E. θ-Defensins: cyclic peptides with endless potential. J. Biol. Chem. 287, 27014–27019 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Craik, D.J. Advances in Botanical Research: Plant Cyclotides Vol. 76 (Academic Press, London, 2015).

  14. 14.

    Craik, D. J. Chemistry. Seamless proteins tie up their loose ends. Science 311, 1563–1564 (2006).

    Article  Google Scholar 

  15. 15.

    Clark, R. J. et al. The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew. Chem. Int. Edn. Engl. 49, 6545–6548 (2010). This study demonstrates orally delivered bioactivity (analgesia) of a cyclic disulfide-rich peptide.

    CAS  Article  Google Scholar 

  16. 16.

    Akcan, M. et al. Chemical re-engineering of chlorotoxin improves bioconjugation properties for tumor imaging and targeted therapy. J. Med. Chem. 54, 782–787 (2011).

    CAS  Article  Google Scholar 

  17. 17.

    Colgrave, M. L. & Craik, D. J. Thermal, chemical, and enzymatic stability of the cyclotide kalata B1: the importance of the cyclic cystine knot. Biochemistry 43, 5965–5975 (2004).

    CAS  Article  Google Scholar 

  18. 18.

    Boy, R. G. et al. Sunflower trypsin inhibitor 1 derivatives as molecular scaffolds for the development of novel peptidic radiopharmaceuticals. Mol. Imaging Biol. 12, 377–385 (2010).

    Article  Google Scholar 

  19. 19.

    Conibear, A. C. et al. The cyclic cystine ladder of theta-defensins as a stable, bifunctional scaffold: a proof-of-concept study using the integrin-binding RGD motif. ChemBioChem 15, 451–459 (2014).

    CAS  Article  Google Scholar 

  20. 20.

    Colgrave, M. L., Korsinczky, M. J., Clark, R. J., Foley, F. & Craik, D. J. Sunflower trypsin inhibitor-1, proteolytic studies on a trypsin inhibitor peptide and its analogs. Biopolymers 94, 665–672 (2010).

    CAS  Article  Google Scholar 

  21. 21.

    Conibear, A. C., Rosengren, K. J., Daly, N. L., Henriques, S. T. & Craik, D. J. The cyclic cystine ladder in θ-defensins is important for structure and stability, but not antibacterial activity. J. Biol. Chem. 288, 10830–10840 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Ojeda, P. G., Chan, L. Y., Poth, A. G., Wang, C. K. & Craik, D. J. The role of disulfide bonds in structure and activity of chlorotoxin. Future Med. Chem. 6, 1617–1628 (2014).

    CAS  Article  Google Scholar 

  23. 23.

    Greenwood, K. P., Daly, N. L., Brown, D. L., Stow, J. L. & Craik, D. J. The cyclic cystine knot miniprotein MCoTI-II is internalized into cells by macropinocytosis. Int. J. Biochem. Cell Biol. 39, 2252–2264 (2007).

    CAS  Article  Google Scholar 

  24. 24.

    Contreras, J., Elnagar, A. Y., Hamm-Alvarez, S. F. & Camarero, J. A. Cellular uptake of cyclotide MCoTI-I follows multiple endocytic pathways. J. Control. Release 155, 134–143 (2011).

    CAS  Article  Google Scholar 

  25. 25.

    Cascales, L. et al. Identification and characterization of a new family of cell-penetrating peptides: cyclic cell-penetrating peptides. J. Biol. Chem. 286, 36932–36943 (2011).

    CAS  Article  Google Scholar 

  26. 26.

    Henriques, S. T. et al. The prototypic cyclotide kalata B1 has a unique mechanism of entering cells. Chem. Biol. 22, 1087–1097 (2015).

    CAS  Article  Google Scholar 

  27. 27.

    D’Souza, C., Henriques, S. T., Wang, C. K. & Craik, D. J. Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1. Eur. J. Med. Chem. 88, 10–18 (2014).

    Article  Google Scholar 

  28. 28.

    Wang, C. K. et al. Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis. ACS Chem. Biol. 9, 156–163 (2014).

    CAS  Article  Google Scholar 

  29. 29.

    Huang, Y. H. et al. Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold. Sci. Rep. 5, 12974 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Chan, L. Y. et al. Engineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds. Blood 118, 6709–6717 (2011).

    CAS  Article  Google Scholar 

  31. 31.

    Aboye, T. et al. Design of a MCoTI-based cyclotide with angiotensin (1-7)-like activity. Molecules 21, 152 (2016).

    Article  Google Scholar 

  32. 32.

    Qiu, Y. et al. An orally active bradykinin B1 receptor antagonist engineered as a bifunctional chimera of sunflower trypsin inhibitor. J. Med. Chem. 60, 504–510 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Sable, R. et al. Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem. Biol. 11, 2366–2374 (2016).

    CAS  Article  Google Scholar 

  34. 34.

    Eliasen, R. et al. Design, synthesis, structural and functional characterization of novel melanocortin agonists based on the cyclotide kalata B1. J. Biol. Chem. 287, 40493–40501 (2012).

    CAS  Article  Google Scholar 

  35. 35.

    Claveria-Gimeno, R., Vega, S., Abian, O. & Velazquez-Campoy, A. A look at ligand binding thermodynamics in drug discovery. Expert Opin. Drug Discov. 12, 363–377 (2017).

    CAS  Article  Google Scholar 

  36. 36.

    Martin, S. F. & Clements, J. H. Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes. Annu. Rev. Biochem. 82, 267–293 (2013).

    CAS  Article  Google Scholar 

  37. 37.

    Ji, Y. et al. In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J. Am. Chem. Soc. 135, 11623–11633 (2013). This study describes a grafted cyclic-peptide scaffold that penetrates cells and modulates an intracellular target.

    CAS  Article  Google Scholar 

  38. 38.

    D’Souza, C. et al. Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer. Biochemistry 55, 396–405 (2016).

    Article  Google Scholar 

  39. 39.

    Huang, Y. H., Chaousis, S., Cheneval, O., Craik, D. J. & Henriques, S. T. Optimization of the cyclotide framework to improve cell penetration properties. Front. Pharmacol. 6, 17 (2015).

    Google Scholar 

  40. 40.

    Wong, C. T. et al. Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew. Chem. Int. Edn. Engl. 51, 5620–5624 (2012). This study demonstrates a grafted peptide that has orally delivered bioactivity against inflammatory pain.

    CAS  Article  Google Scholar 

  41. 41.

    Thell, K. et al. Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis. Proc. Natl Acad. Sci. USA 113, 3960–3965 (2016).

    CAS  Article  Google Scholar 

  42. 42.

    White, T. R. et al. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat. Chem. Biol. 7, 810–817 (2011).

    CAS  Article  Google Scholar 

  43. 43.

    Nielsen, D. S. et al. Improving on nature: making a cyclic heptapeptide orally bioavailable. Angew. Chem. Int. Edn. Engl. 53, 12059–12063 (2014).

    CAS  Article  Google Scholar 

  44. 44.

    Wang, C. K. et al. Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients. Proc. Natl Acad. Sci. USA 111, 17504–17509 (2014).

    CAS  Article  Google Scholar 

  45. 45.

    Frost, J. R., Scully, C. C. & Yudin, A. K. Oxadiazole grafts in peptide macrocycles. Nat. Chem. 8, 1105–1111 (2016).

    CAS  Article  Google Scholar 

  46. 46.

    Biron, E. et al. Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew. Chem. Int. Edn. Engl. 47, 2595–2599 (2008).

    CAS  Article  Google Scholar 

  47. 47.

    Harris, L. A. Constipation: linaclotide–a stimulating new drug for chronic constipation. Nat. Rev. Gastroenterol. Hepatol. 7, 365–366 (2010).

    CAS  Article  Google Scholar 

  48. 48.

    Zhang, J., Yamaguchi, S. & Nagamune, T. Sortase A-mediated synthesis of ligand-grafted cyclized peptides for modulating a model protein-protein interaction. Biotechnol. J. 10, 1499–1505 (2015).

    CAS  Article  Google Scholar 

  49. 49.

    de Veer, S. J., Wang, C. K., Harris, J. M., Craik, D. J. & Swedberg, J. E. Improving the selectivity of engineered protease inhibitors: optimizing the P2 primer residue using a versatile cyclic peptide library. J. Med. Chem. 58, 8257–8268 (2015).

    Article  Google Scholar 

  50. 50.

    Quimbar, P. et al. High-affinity cyclic peptide matriptase inhibitors. J. Biol. Chem. 288, 13885–13896 (2013).

    CAS  Article  Google Scholar 

  51. 51.

    Swedberg, J. E. et al. Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists. Eur. J. Med. Chem. 103, 175–184 (2015).

    CAS  Article  Google Scholar 

  52. 52.

    Gavenonis, J., Sheneman, B. A., Siegert, T. R., Eshelman, M. R. & Kritzer, J. A. Comprehensive analysis of loops at protein-protein interfaces for macrocycle design. Nat. Chem. Biol. 10, 716–722 (2014).

    CAS  Article  Google Scholar 

  53. 53.

    Bhardwaj, G. et al. Accurate de novo design of hyperstable constrained peptides. Nature 538, 329–335 (2016).

    CAS  Article  Google Scholar 

  54. 54.

    Wang, C. K., Northfield, S. E., Huang, Y. H., Ramos, M. C. & Craik, D. J. Inhibition of tau aggregation using a naturally-occurring cyclic peptide scaffold. Eur. J. Med. Chem. 109, 342–349 (2016).

    CAS  Article  Google Scholar 

  55. 55.

    Chan, L. Y., Craik, D. J. & Daly, N. L. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy. Sci. Rep. 6, 35347 (2016). This study shows an example of grafting two epitopes that target different pathways onto a single scaffold.

    CAS  Article  Google Scholar 

  56. 56.

    Gunasekera, S. et al. Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J. Med. Chem. 51, 7697–7704 (2008).

    CAS  Article  Google Scholar 

  57. 57.

    Aboye, T. L. et al. Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity. J. Med. Chem. 55, 10729–10734 (2012).

    CAS  Article  Google Scholar 

  58. 58.

    Sommerhoff, C. P. et al. Engineered cystine knot miniproteins as potent inhibitors of human mast cell tryptase β. J. Mol. Biol. 395, 167–175 (2010).

    CAS  Article  Google Scholar 

  59. 59.

    Zoller, F. et al. Combination of phage display and molecular grafting generates highly specific tumor-targeting miniproteins. Angew. Chem. Int. Edn. Engl. 51, 13136–13139 (2012).

    CAS  Article  Google Scholar 

  60. 60.

    Glotzbach, B. et al. Combinatorial optimization of cystine-knot peptides towards high-affinity inhibitors of human matriptase-1. PLoS One 8, e76956 (2013).

    CAS  Article  Google Scholar 

  61. 61.

    Getz, J. A., Rice, J. J. & Daugherty, P. S. Protease-resistant peptide ligands from a knottin scaffold library. ACS Chem. Biol. 6, 837–844 (2011).

    CAS  Article  Google Scholar 

  62. 62.

    Getz, J. A., Cheneval, O., Craik, D. J. & Daugherty, P. S. Design of a cyclotide antagonist of neuropilin-1 and -2 that potently inhibits endothelial cell migration. ACS Chem. Biol. 8, 1147–1154 (2013).

    CAS  Article  Google Scholar 

  63. 63.

    Kimura, R. H. et al. Pharmacokinetically stabilized cystine knot peptides that bind alpha-v-beta-6 integrin with single-digit nanomolar affinities for detection of pancreatic cancer. Clin. Cancer Res. 18, 839–849 (2012).

    CAS  Article  Google Scholar 

  64. 64.

    Cobos Caceres, C. et al. An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease. J. Biol. Chem. 292, 10288–10294 (2017).

    Article  Google Scholar 

  65. 65.

    Li, K., Condurso, H. L., Li, G., Ding, Y. & Bruner, S. D. Structural basis for precursor protein-directed ribosomal peptide macrocyclization. Nat. Chem. Biol. 12, 973–979 (2016).

    Article  Google Scholar 

  66. 66.

    Repka, L. M., Chekan, J. R., Nair, S. K. & van der Donk, W. A. Mechanistic understanding of lanthipeptide biosynthetic enzymes. Chem. Rev. 117, 5457–5520 (2017).

    CAS  Article  Google Scholar 

  67. 67.

    Nguyen, G. K. et al. Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis. Nat. Chem. Biol. 10, 732–738 (2014).

    CAS  Article  Google Scholar 

  68. 68.

    Harris, K. S. et al. Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase. Nat. Commun. 6, 10199 (2015).

    CAS  Article  Google Scholar 

  69. 69.

    Maric, H. M. et al. Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission. Nat. Chem. Biol. 13, 153–160 (2017).

    CAS  Article  Google Scholar 

  70. 70.

    Kintzing, J. R. & Cochran, J. R. Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles. Curr. Opin. Chem. Biol. 34, 143–150 (2016).

    CAS  Article  Google Scholar 

  71. 71.

    Bonning, B. C. et al. Toxin delivery by the coat protein of an aphid-vectored plant virus provides plant resistance to aphids. Nat. Biotechnol. 32, 102–105 (2014).

    CAS  Article  Google Scholar 

  72. 72.

    Pappas, C. G. et al. Dynamic peptide libraries for the discovery of supramolecular nanomaterials. Nat. Nanotechnol. 11, 960–967 (2016).

    CAS  Article  Google Scholar 

  73. 73.

    Heinis, C., Rutherford, T., Freund, S. & Winter, G. Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat. Chem. Biol. 5, 502–507 (2009).

    CAS  Article  Google Scholar 

  74. 74.

    Passioura, T., Katoh, T., Goto, Y. & Suga, H. Selection-based discovery of druglike macrocyclic peptides. Annu. Rev. Biochem. 83, 727–752 (2014).

    CAS  Article  Google Scholar 

  75. 75.

    Thongyoo, P., Roqué-Rosell, N., Leatherbarrow, R. J. & Tate, E. W. Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides. Org. Biomol. Chem. 6, 1462–1470 (2008).

    CAS  Article  Google Scholar 

  76. 76.

    Swedberg, J. E. et al. Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chem. Biol. 16, 633–643 (2009).

    CAS  Article  Google Scholar 

  77. 77.

    Fittler, H., Avrutina, O., Empting, M. & Kolmar, H. Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor. J. Pept. Sci. 20, 415–420 (2014).

    CAS  Article  Google Scholar 

  78. 78.

    Chan, L. Y., Craik, D. J. & Daly, N. L. Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration. Biosci. Rep. 35, e00270 (2015).

    Article  Google Scholar 

  79. 79.

    Jendrny, C. & Beck-Sickinger, A. G. Inhibition of kallikrein-related peptidases 7 and 5 by grafting serpin reactive-center loop sequences onto sunflower trypsin inhibitor-1 (SFTI-1). ChemBioChem 17, 719–726 (2016).

    CAS  Article  Google Scholar 

  80. 80.

    Conibear, A. C. et al. Approaches to the stabilization of bioactive epitopes by grafting and peptide cyclization. Biopolymers 106, 89–100 (2016).

    CAS  Article  Google Scholar 

  81. 81.

    Clark, R. J., Daly, N. L. & Craik, D. J. Structural plasticity of the cyclic-cystine-knot framework: implications for biological activity and drug design. Biochem. J. 394, 85–93 (2006).

    CAS  Article  Google Scholar 

  82. 82.

    Thongyoo, P., Bonomelli, C., Leatherbarrow, R. J. & Tate, E. W. Potent inhibitors of β-tryptase and human leukocyte elastase based on the MCoTI-II scaffold. J. Med. Chem. 52, 6197–6200 (2009).

    CAS  Article  Google Scholar 

  83. 83.

    Swedberg, J. E. et al. Substrate-guided design of selective FXIIa inhibitors based on the plant-derived Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) scaffold. J. Med. Chem. 59, 7287–7292 (2016).

    CAS  Article  Google Scholar 

  84. 84.

    Swedberg, J. E., Li, C. Y., de Veer, S. J., Wang, C. K. & Craik, D. J. Design of potent and selective cathepsin G inhibitors based on the sunflower trypsin inhibitor-1 scaffold. J. Med. Chem. 60, 658–667 (2017).

    CAS  Article  Google Scholar 

  85. 85.

    Maaß, F. et al. Cystine-knot peptides targeting cancer-relevant human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J. Pept. Sci. 21, 651–660 (2015).

    Article  Google Scholar 

  86. 86.

    Jagadish, K. et al. Recombinant expression and phenotypic screening of a bioactive cyclotide against α-synuclein-induced cytotoxicity in baker’s yeast. Angew. Chem. Int. Edn. Engl. 54, 8390–8394 (2015).

    CAS  Article  Google Scholar 

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Acknowledgements

D.J.C. is an Australian Research Council Australian Laureate (FL150100146). Work in our laboratory on peptide scaffolds is supported by grants from the Australian Research Council (DP150100443) and the National Health and Medical Research Council (APP1107403 and APP1060225).

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Wang, C.K., Craik, D.J. Designing macrocyclic disulfide-rich peptides for biotechnological applications. Nat Chem Biol 14, 417–427 (2018). https://doi.org/10.1038/s41589-018-0039-y

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