Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles

Current Opinion in Chemical Biology

Volumn 34, Issue , 2016, Pages 143-150

  Kintzing, James R ^a   Cochran, Jennifer R ^a  

^a STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG; KNOTTIN; MOLECULAR SCAFFOLD; DRUG CARRIER; PEPTIDE;

BIOLOGICAL ACTIVITY; CYSTINE KNOT MOTIF; DRUG DELIVERY SYSTEM; DRUG TARGETING; HUMAN; MOLECULAR IMAGING; NONHUMAN; PROTEIN ENGINEERING; PROTEIN FOLDING; REVIEW; THERAPY; ANIMAL; CHEMISTRY; DIAGNOSIS;

ANIMALS; CYSTINE-KNOT MINIPROTEINS; DIAGNOSIS; DRUG CARRIERS; HUMANS; PEPTIDES; PROTEIN ENGINEERING; THERAPEUTICS;

EID: 84987973964     PISSN: 13675931     EISSN: 18790402     Source Type: Journal    
DOI: 10.1016/j.cbpa.2016.08.022     Document Type: Review

References (49)

1. 1 Ackerman, S.E., Currier, N.V., Bergen, J.M., Cochran, J.R., Cystine-knot peptides: emerging tools for cancer imaging and therapy. Expert Rev Proteomics 11 (2014), 561–572.
2. 2 Zhu, S., Darbon, H., Verdonck, F., Tytgat, J., Evolutionary origin of inhibitor cystine knot peptides. FASEB 17 (2003), 1765–1767.
3. 3 Layer, P., Stanghellini, V., Review article: linaclotide for the management of irritable bowel syndrome with constipation. Aliment Pharmacol Ther 39 (2014), 371–384.
4. 4 King, G.F., Venoms as a platform for human drugs: translating toxins into therapeutics. Expert Opin Biol Ther 11 (2011), 1469–1484.
5. 5 Kolmar, H., Alternative binding proteins: biological activity and therapeutic potential of cystine-knot miniproteins. FEBS J 275 (2008), 2684–2690.
6. 6 Daly, N.L., Craik, D.J., Bioactive cystine knot proteins. Curr Opin Chem Biol 15 (2011), 362–368.
7. 7 Iyer, S., Acharya, K.R., Tying the knot: the cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines. FEBS J 278 (2011), 4304–4322.
8. 8• Herzig, V., King, G.F., The cystine knot is responsible for the exceptional stability of the insecticidal spider toxin omega-hexatoxin-Hv1a. Toxins (Basel) 7 (2015), 4366–4380 Rigorous study showing that the Hv1a toxin was highly stable when subjected to temperatures up to 75 °C, pH values as low as 1, various organic solvents, enzymatic digestion, and incubation in insect hemolymph and human plasma. The cystine knot of Hv1a was shown to be responsible for this remarkable thermal, chemical and proteolytic stability.
9. 9 Kikuchi, K., Sugiura, M., Kimura, T., High proteolytic resistance of spider-derived inhibitor cystine knots. Int J Pept, 2015, 2015, 537508, 10.1155/2015/537508.
10. 10 Clark, R.J., Craik, D.J., Engineering cyclic peptide toxins. Methods Enzymol 503 (2012), 57–74.
11. 11 Klint, J.K., Senff, S., Saez, N.J., Seshadri, R., Lau, H.Y., Bende, N.S., Undheim, E.A., Rash, L.D., Mobli, M., King, G.F., Production of recombinant disulfide-rich venom peptides for structural and functional analysis via expression in the periplasm of E. coli. PLOS ONE, 8, 2013, e63865.
12. 12 Moore, S.J., Cochran, J.R., Engineering knottins as novel binding agents. Methods Enzymol 503 (2012), 223–251.
13. 13 Glotzbach, B., Reinwarth, M., Weber, N., Fabritz, S., Tomaszowski, M., Fittler, H., Christmann, A., Avrutina, O., Kolmar, H., Combinatorial optimization of cystine-knot peptides towards high-affinity inhibitors of human matriptase-1. PLOS ONE, 8, 2013, e76956.
14. 14 Maass, F., Wustehube-Lausch, J., Dickgiesser, S., Valldorf, B., Reinwarth, M., Schmoldt, H.U., Daneschdar, M., Avrutina, O., Sahin, U., Kolmar, H., Cystine-knot peptides targeting cancer-relevant human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Pept Sci 21 (2015), 651–660.
15. 15•• Huang, Y.H., Henriques, S.T., Wang, C.K., Thorstholm, L., Daly, N.L., Kaas, Q., Craik, D.J., Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold. Sci Rep, 5, 2015, 12974, 10.1038/srep12974 Engineered cyclotides as candidates for treating chronic myeloid leukemia were created by incorporating sequences from ablitide, the optimal substrate of the Abl kinase, into loop 1 or 6 of MCoTI-II. The resulting substrate-competitive inhibitors could penetrate cells and were promising inhibitors against Abl and an Abl kinase harboring a multidrug resistant mutation.
16. 16 D'Souza, C., Henriques, S.T., Wang, C.K., Cheneval, O., Chan, L.Y., Bokil, N.J., Sweet, M.J., Craik, D.J., Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer. Biochemistry 55 (2016), 396–405.
17. 17•• Aboye, T., Meeks, C.J., Majumder, S., Shekhtman, A., Rodgers, K., Camarero, J.A., Design of a MCoTI-based cyclotide with angiotensin (1-7)-like activity. Molecules, 21, 2016, 12974, 10.1038/srep12974 A peptide analog was grafted onto loop 6 of MCoTI-I to create a peptide-based activator of the MAS1 receptor for treatment of cancer and myocardial infarction. Unique isopeptide bonds were used to preserve the α-amino and C-terminal carboxylate groups of AT1-7, which are required for activity.
18. 18 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, 2015 e00270.
19. 19 Sankaran, S., de Ruiter, M., Cornelissen, J.J., Jonkheijm, P., Supramolecular surface immobilization of knottin derivatives for dynamic display of high affinity binders. Bioconjug Chem 26 (2015), 1972–1980.
20. 20 Veiseh, M., Gabikian, P., Bahrami, S.B., Veiseh, O., Zhang, M., Hackman, R.C., Ravanpay, A.C., Stroud, M.R., Kusuma, Y., Hansen, S.J., et al. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res 67 (2007), 6882–6888.
21. 21•• Fidel, J., Kennedy, K.C., Dernell, W.S., Hansen, S., Wiss, V., Stroud, M.R., Molho, J.I., Knoblaugh, S.E., Meganck, J., Olson, J.M., et al. Preclinical validation of the utility of BLZ-100 in providing fluorescence contrast for imaging spontaneous solid tumors. Cancer Res 75 (2015), 4283–4291 Preclinical proof of concept for use of the Tumor Paint BLZ-100 as an imaging contrast agent administered to canine patients before surgery for spontaneous tumors. Subcutaneous soft tissue sarcomas were labeled with the highest fluorescence intensity and the greatest contrast compared to adenocarcinomas, squamous cell carcinomas, and mast cell tumors.
22. 22 Moore, S.J., Hayden Gephart, M., Bergen, J.M., Su, Y., Rayburn, H., Scott, M., Cochran, J.R., Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma. PNAS 110 (2013), 14598–14603.
23. 23 Meng, X.X., Wan, J.Q., Jing, M., Zhao, S.G., Cai, W., Liu, E.Z., Specific targeting of gliomas with multifunctional superparamagnetic iron oxide nanoparticle optical and magnetic resonance imaging contrast agents. Acta Pharmacol Sin 28 (2007), 2019–2026.
24. 24 Willmann, J.K., Kimura, R.H., Deshpande, N., Lutz, A.M., Cochran, J.R., Gambhir, S.S., Targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with contrast microbubbles conjugated to integrin-binding knottin peptides. J Nucl Med 51 (2010), 433–440.
25. 25 Jiang, L., Tu, Y., Kimura, R.H., Habte, F., Chen, H., Cheng, K., Shi, H., Gambhir, S.S., Cheng, Z., 64Cu-labeled divalent cystine knot peptide for imaging carotid atherosclerotic plaques. J Nucl Med 56 (2015), 939–944.
26. 26 Dardevet, L., Rani, D., Aziz, T.A., Bazin, I., Sabatier, J.M., Fadl, M., Brambilla, E., De Waard, M., Chlorotoxin: a helpful natural scorpion peptide to diagnose glioma and fight tumor invasion. Toxins (Basel) 7 (2015), 1079–1101.
27. 27 Graf, N., Mokhtari, T.E., Papayannopoulos, I.A., Lippard, S.J., Platinum(IV)–chlorotoxin (CTX) conjugates for targeting cancer cells. J Inorg Biochem 110 (2012), 58–63.
28. 28 Cox, N., Kintzing, J.R., Smith, M., Grant, G.A., Cochran, J.R., Integrin-targeting knottin peptide-drug conjugates are potent inhibitors of tumor cell proliferation. Angew Chem Int Ed Engl 55 (2016), 9894–9897.
29. 29•• Currier, N.V., Ackerman, S.E., Kintzing, J.R., Chen, R., Interrante, M.F., Steiner, A., Sato, A.K., Cochran, J.R., Targeted drug delivery with an integrin-binding knottin-Fc-MMAF conjugate produced by cell-free-protein synthesis. Mol Cancer Ther 15 (2016), 1291–1300 Knottin-Fc drug conjugates (KFDCs), attached to monomethyl-auristatin-F through a chemical linker, were synthesized via a non-natural amino acid incorporated during cell-free protein synthesis. The KFDC significantly prolonged tumor regression and survival in a xenograft model compared to a non-targeted conjugate or drug alone, thus providing a basis for further development of KFDCs for targeted drug delivery applications.
30. 30 Krause, S., Schmoldt, H.U., Wentzel, A., Ballmaier, M., Friedrich, K., Kolmar, H., Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists. FEBS J 274 (2007), 86–95.
31. 31 Kim, J.W., Cochran, F.V., Cochran, J.R., A chemically cross-linked knottin dimer binds integrins with picomolar affinity and inhibits tumor cell migration and proliferation. J Am Chem Soc 137 (2015), 6–9.
32. 32 Gowd, K.H., Yarotskyy, V., Elmslie, K.S., Skalicky, J.J., Olivera, B.M., Bulaj, G., Site-specific effects of diselenide bridges on the oxidative folding of a cystine knot peptide, omega-selenoconotoxin GVIA. Biochemistry 49 (2010), 2741–2752.
33. 33 Walewska, A., Zhang, M.M., Skalicky, J.J., Yoshikami, D., Olivera, B.M., Bulaj, G., Integrated oxidative folding of cysteine/selenocysteine containing peptides: improving chemical synthesis of conotoxins. Angew Chem Int Ed Engl 48 (2009), 2221–2224.
34. 34• Reinwarth, M., Avrutina, O., Fabritz, S., Kolmar, H., Fragmentation follows structure: top-down mass spectrometry elucidates the topology of engineered cystine-knot miniproteins. PLOS ONE, 9, 2014, e108626 An analytical method is presented for disulfide pattern determination, and hence structural characterization, of oxidized and bioactive cystine knot peptides using mass spectrometry. The fragmentation patterns were shown to be dependent on the folding state of the peptides.
35. 35 Craik, D.J., Fairlie, D.P., Liras, S., Price, D., The future of peptide-based drugs. Chem Biol Drug Des 81 (2013), 136–147.
36. 36 Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A.Y., Neamati, N., Shekhtman, A., Camarero, J.A., In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J Am Chem Soc 135 (2013), 11623–11633.
37. 37 Verdine, G.L., Walensky, L.D., The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res 13 (2007), 7264–7270.
38. 38 Weidle, U.H., Auer, J., Brinkmann, U., Georges, G., Tiefenthaler, G., The emerging role of new protein scaffold-based agents for treatment of cancer. Cancer Genomics Proteomics 13 (2013), 155–168.
39. 39 Clark, R.J., Jensen, J., Nevin, S.T., Callaghan, B.P., Adams, D.J., Craik, D.J., The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew Chem Int Ed 49 (2010), 6545–6548.
40. 40 Wong, C.T., Rowlands, D.K., Wong, C.H., Lo, T.W., Nguyen, G.K., Li, H.Y., Tam, J.P., Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew Chem Int Ed Engl 51 (2012), 5620–5624.
41. 41 Moore, S.J., Leung, C.L., Norton, H.K., Cochran, J.R., Engineering agatoxin, a cystine-knot peptide from spider venom, as a molecular probe for in vivo tumor imaging. PLOS ONE, 8, 2013, e60498.
42. 42 Kimura, R.H., Levin, A.M., Cochran, F.V., Cochran, J.R., Engineered cystine knot peptides that bind alphavbeta3, alphavbeta5, and alpha5beta1 integrins with low-nanomolar affinity. Proteins 77 (2009), 359–369.
43. 43 Silverman, A.P., Levin, A.M., Lahti, J.L., Cochran, J.R., Engineered cystine-knot peptides that bind alpha(v)beta(3) integrin with antibody-like affinities. J Mol Biol 385 (2009), 1064–1075.
44. 44 Silverman, A.P., Kariolis, M.S., Cochran, J.R., Cystine-knot peptides engineered with specificities for alpha(IIb)beta(3) or alpha(IIb)beta(3) and alpha(v)beta(3) integrins are potent inhibitors of platelet aggregation. J Mol Recogn 24 (2011), 127–135.
45. 45 Gunasekera, S., Foley, F.M., Clark, R.J., Sando, L., Fabri, L.J., Craik, D.J., Daly, N.L., Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J Med Chem 51 (2008), 7697–7704.
46. 46 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 (2013), 1147–1154.
47. 47 Aboye, T.L., Ha, H., Majumder, S., Christ, F., Debyser, Z., Shekhtman, A., Neamati, N., Camarero, J.A., Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity. J Med Chem 55 (2012), 10729–10734.
48. 48 Kimura, R.H., Teed, R., Hackel, B.J., Pysz, M.A., Chuang, C.Z., Sathirachinda, A., Willmann, J.K., Gambhir, S.S., 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 (2012), 839–849.
49. 49 Sommerhoff, C.P., Avrutina, O., Schmoldt, H.U., Gabrijelcic-Geiger, D., Diederichsen, U., Kolmar, H., Engineered cystine knot miniproteins as potent inhibitors of human mast cell tryptase beta. J Mol Biol 395 (2010), 167–175.