Biological diversity and therapeutic potential of natural and engineered cystine knot miniproteins

Current Opinion in Pharmacology

Volumn 9, Issue 5, 2009, Pages 608-614

  Kolmar, Harald ^a  

^a DARMSTADT UNIVERSITY OF TECHNOLOGY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1,4,7,10 TETRAAZACYCLODODECANE 1,4,7,10 TETRAACETIC ACID; AGOUTI RELATED PROTEIN; CHARYBDOTOXIN; CONOTOXIN; COPPER 64; CYCLOTIDE; CYSTINE KNOT MINIPROTEIN; DISULFIDE; ECBALLIUM ELATERIUM EXTRACT; ELASTASE INHIBITOR; FIBRINOGEN; OMEGA CONOTOXIN MVIIA; PENTAPEPTIDE; PROTEIN DERIVATIVE; PSALMOPEOTOXIN I; PSALMOPEOTOXIN II; SERINE PROTEINASE INHIBITOR; SPIDER VENOM; TRYPSIN INHIBITOR; UNCLASSIFIED DRUG; VASCULOTROPIN INHIBITOR;

AMINO ACID COMPOSITION; ANTIPROTOZOAL ACTIVITY; BIODIVERSITY; BRAIN INJURY; CHILDBIRTH; CHRONIC PAIN; CLINICAL TRIAL; COMBINATORIAL CHEMISTRY; COMBINATORIAL LIBRARY; DISULFIDE BOND; DRUG DESIGN; DRUG STABILITY; HUMAN; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PLASMODIUM FALCIPARUM; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN ENGINEERING; PROTEIN STRUCTURE; REVIEW; SOLID PHASE SYNTHESIS; THERMOSTABILITY; THROMBOCYTE AGGREGATION INHIBITION; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; COMBINATORIAL CHEMISTRY TECHNIQUES; CYCLOTIDES; CYSTINE KNOT MOTIFS; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PEPTIDE LIBRARY; PEPTIDES; PROTEIN CONFORMATION; PROTEIN DENATURATION; PROTEIN ENGINEERING; PROTEIN STABILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 70349414437     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.coph.2009.05.004     Document Type: Review

References (50)

1. Chiche L., Heitz A., Gelly J.C., Gracy J., Chau P.T., Ha P.T., Hernandez J.F., and Le-Nguyen D. Squash inhibitors: from structural motifs to macrocyclic knottins. Curr Protein Pept Sci 5 (2004) 341-349
2. Werle M., Kafedjiiski K., Kolmar H., and Bernkop-Schnurch A. Evaluation and improvement of the properties of the novel cystine-knot microprotein McoEeTI for oral administration. Int J Pharm 332 (2007) 72-79
3. Heitz A., Avrutina O., Le-Nguyen D., Diederichsen U., Hernandez J.F., Gracy J., Kolmar H., and Chiche L. Knottin cyclization: impact on structure and dynamics. BMC Struct Biol 8 (2008) 54. A comparative investigation on the stability and flexibility of circular and linear knottins indicates that in contrast to what could have been intuitively expected, cyclization does not contribute to stability or flexibility. Unfolding simulations showed, however, that cyclization is a stabilizing factor in strongly denaturing conditions.
4. 64Cu-DOTA-conjugated knottin peptides generated relatively low levels of nonspecific liver uptake and were stable in mouse serum. In vivo metabolite analysis showed minimal degradation in the blood or tumor upon injection. These data indicate that knottin peptides show great potential as clinical diagnostics for a variety of cancers.
5. Wang C.K., Hu S.H., Martin J.L., Sjogren T., Hajdu J., Bohlin L., Claeson P., Goransson U., Rosengren K.J., Tang J., Tan N.H., et al. Combined X-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as drug scaffold. J Biol Chem 284 (2009) 10672-10683
6. Werle M., Kolmar H., Albrecht R., and Bernkop-Schnurch A. Characterisation of the barrier caused by luminally secreted gastro-intestinal proteolytic enzymes for two novel cystine-knot microproteins. Amino Acids 35 (2008) 195-200
7. Werle M., Schmitz T., Huang H.L., Wentzel A., Kolmar H., and Bernkop-Schnurch A. The potential of cystine-knot microproteins as novel pharmacophoric scaffolds in oral peptide drug delivery. J Drug Target 14 (2006) 137-146. The applicability of knottins for oral peptide delivery was investigated. Several miniproteins were analyzed regarding their stability toward the most important gastrointestinal secreted and membrane-bound proteases in physiological concentrations. In addition, their permeation behavior through freshly excised rat intestinal mucosa was evaluated. It was found that pepsin and elastase cause no or only minor degradation whereas trypsin and chymotrypsin degrade extensively. Removing the chymotrypsin cleavage site from a knottin, however, led to stabilization toward this protease. Two of the three evaluated knottins were stable against membrane-bound proteases. This study indicates that cystine knot peptides are promising novel pharmacophoric scaffolds for oral peptide delivery.
8. Gruber C.W., Elliott A.G., Ireland D.C., Delprete P.G., Dessein S., Goransson U., Trabi M., Wang C.K., Kinghorn A.B., Robbrecht E., and Craik D.J. Distribution and evolution of circular miniproteins in flowering plants. Plant Cell 20 (2008) 2471-2483
9. Craik D.J., Cemazar M., and Daly N.L. The chemistry and biology of cyclotides. Curr Opin Drug Discov Dev 10 (2007) 176-184
10. Gunasekera S., Daly N.L., Clark R.J., and Craik D.J. Dissecting the oxidative folding of circular cystine knot miniproteins. Antioxid Redox Signal 11 (2009) 971-980
11. Cemazar M., Joshi A., Daly N.L., Mark A.E., and Craik D.J. The structure of a two-disulfide intermediate assists in elucidating the oxidative folding pathway of a cyclic cystine knot protein. Structure 16 (2008) 842-851
12. Cemazar M., Gruber C.W., and Craik D.J. Oxidative folding of cyclic cystine knot proteins. Antioxid Redox Signal 10 (2008) 103-111
13. Wentzel A., Christmann A., Kratzner R., and Kolmar H. Sequence requirements of the GPNG beta-turn of the Ecballium elaterium trypsin inhibitor II explored by combinatorial library screening. J Biol Chem 274 (1999) 21037-21043
14. Gruber C.W., Cemazar M., Clark R.J., Horibe T., Renda R.F., Anderson M.A., and Craik D.J. A novel plant protein-disulfide isomerase involved in the oxidative folding of cystine knot defense proteins. J Biol Chem 282 (2007) 20435-20446
15. Craik D.J., and Daly N.L. Oxidative folding of the cystine knot motif in cyclotide proteins. Protein Pept Lett 12 (2005) 147-152
16. Craik D.J., and Daly N.L. NMR as a tool for elucidating the structures of circular and knotted proteins. Mol Biosyst 3 (2007) 257-265
17. Gelly J.C., Gracy J., Kaas Q., Le-Nguyen D., Heitz A., and Chiche L. The KNOTTIN website and database: a new information system dedicated to the knottin scaffold. Nucleic Acids Res 32 (2004) D156-159
18. Williams J.A., Day M., and Heavner J.E. Ziconotide: an update and review. Expert Opin Pharmacother 9 (2008) 1575-1583
19. Perez-Pinzon M.A., Yenari M.A., Sun G.H., Kunis D.M., and Steinberg G.K. SNX-111, a novel, presynaptic N-type calcium channel antagonist, is neuroprotective against focal cerebral ischemia in rabbits. J Neurol Sci 153 (1997) 25-31
20. Massote P.D., Pinheiro A.C., Fonseca C.G., Prado M.A., Guimaraes A.L., Massensini A.R., and Gomez M.V. Protective effect of retinal ischemia by blockers of voltage-dependent calcium channels and intracellular calcium stores. Cell Mol Neurobiol 28 (2008) 847-856
21. Pallaghy P.K., Nielsen K.J., Craik D.J., and Norton R.S. A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides. Protein Sci 3 (1994) 1833-1839
22. Siemens J., Zhou S., Piskorowski R., Nikai T., Lumpkin E.A., Basbaum A.I., King D., and Julius D. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444 (2006) 208-212. In this paper, it was shown for the first time that venom from a tarantula that is native to the West Indies contains three cystine knot peptides that target the capsaicin receptor TRPV1 and act as TRPV1 agonists. These knottins may provide new tools for understanding the mechanisms of TRP channel gating.
23. Pimentel C., Choi S.J., Chagot B., Guette C., Camadro J.M., and Darbon H. Solution structure of PcFK1, a spider peptide active against Plasmodium falciparum. Protein Sci 15 (2006) 628-634
24. Choi S.J., Parent R., Guillaume C., Deregnaucourt C., Delarbre C., Ojcius D.M., Montagne J.J., Celerier M.L., Phelipot A., Amiche M., Molgo J., et al. Isolation and characterization of Psalmopeotoxin I and II: two novel antimalarial peptides from the venom of the tarantula Psalmopoeus cambridgei. FEBS Lett 572 (2004) 109-117
25. Gran L., Sandberg F., and Sletten K. Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine. J Ethnopharmacol 70 (2000) 197-203
26. Gran L., Sletten K., and Skjeldal L. Cyclic peptides from Oldenlandia affinis DC. Molecular and biological properties. Chem Biodivers 5 (2008) 2014-2022
27. Daly N.L., Clark R.J., Plan M.R., and Craik D.J. Kalata B8, a novel antiviral circular protein, exhibits conformational flexibility in the cystine knot motif. Biochem J 393 (2006) 619-626. A new cyclotide, kalata B8, was isolated which displays an inherent structural flexibility of the cystine knot core uncommon to cyclotides. Kalata B8 displays anti-HIV activity but unlike other related cyclotides lacks hemolytic activity. This indicates that the hemolytic activity often found in cyclotides can be uncoupled from other biological activities.
28. Wilczynski A.M., Joseph C.G., and Haskell-Luevano C. Current trends in the structure-activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist. Med Res Rev 25 (2005) 545-556
29. Jackson P.J., McNulty J.C., Yang Y.K., Thompson D.A., Chai B., Gantz I., Barsh G.S., and Millhauser G.L. Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity. Biochemistry 41 (2002) 7565-7572
30. Yu B., and Millhauser G.L. Chemical disulfide mapping identifies an inhibitor cystine knot in the agouti signaling protein. FEBS Lett 581 (2007) 5561-5565
31. Colgrave M.L., and Craik D.J. Thermal, chemical, and enzymatic stability of the cyclotide kalata B1: the importance of the cyclic cystine knot. Biochemistry 43 (2004) 5965-5975
32. Ireland D.C., Colgrave M.L., and Craik D.J. A novel suite of cyclotides from Viola odorata: sequence variation and the implications for structure, function and stability. Biochem J 400 (2006) 1-12
33. Drakopoulou E., Zinn-Justin S., Guenneugues M., Gilqin B., Menez A., and Vita C. Changing the structural context of a functional beta-hairpin. Synthesis and characterization of a chimera containing the curaremimetic loop of a snake toxin in the scorpion alpha/beta scaffold. J Biol Chem 271 (1996) 11979-11987
34. Vita C., Drakopoulou E., Vizzavona J., Rochette S., Martin L., Menez A., Roumestand C., Yang Y.S., Ylisastigui L., Benjouad A., and Gluckman J.C. Rational engineering of a miniprotein that reproduces the core of the CD4 site interacting with HIV-1 envelope glycoprotein. Proc Natl Acad Sci U S A 96 (1999) 13091-13096
35. Martin L., Stricher F., Misse D., Sironi F., Pugniere M., Barthe P., Prado-Gotor R., Freulon I., Magne X., Roumestand C., Menez A., et al. Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes. Nat Biotechnol 21 (2003) 71-76
36. Li H., Song H., Heredia A., Le N., Redfield R., Lewis G.K., and Wang L.X. Synthetic bivalent CD4-mimetic miniproteins show enhanced anti-HIV activity over the monovalent miniprotein. Bioconjug Chem 15 (2004) 783-789
37. Stricher F., Huang C.C., Descours A., Duquesnoy S., Combes O., Decker J.M., Kwon Y.D., Lusso P., Shaw G.M., Vita C., Kwong P.D., et al. Combinatorial optimization of a CD4-mimetic miniprotein and cocrystal structures with HIV-1 gp120 envelope glycoprotein. J Mol Biol 382 (2008) 510-524. Combinatorial chemistry was applied to optimize a CD4 mimetic knottin into which the HIV-1 gp120 binding surface of the CD4 receptor was grafted. Iterative deconvolution of generated libraries produced a derivative that had been optimized at four positions and displayed fourfold to sixfold improvement in affinity for gp120 to a level about threefold tighter than that of CD4 itself. These results demonstrate the potential of combinatorial chemistry to optimize cystine knot miniproteins.
38. Reiss S., Sieber M., Oberle V., Wentzel A., Spangenberg P., Claus R., Kolmar H., and Losche W. Inhibition of platelet aggregation by grafting RGD and KGD sequences on the structural scaffold of small disulfide-rich proteins. Platelets 17 (2006) 153-157
39. Gunasekera S., Foley F.M., Clark R.J., Sando L., Fabri L.J., Craik D.J., and 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. A novel VEGF-A antagonists was developed by grafting a peptide epitope involved in VEGF-A antagonism onto the framework of a cyclotide. The variant displayed biological activity in an in vitro VEGF-A antagonism assay at low micromolar concentration and the in vitro stability of the target peptide was found to be markedly increased.
40. 50 values in the picomolar range that were also active in vivo. This shows that miniprotein dimerization and oligomerization is a promising strategy for pharmaceutical interference with other receptors that are activated by ligand-induced dimerization.
41. Hilpert K., Wessner H., Schneider-Mergener J., Welfle K., Misselwitz R., Welfle H., Hocke A.C., Hippenstiel S., and Hohne W. Design and characterization of a hybrid miniprotein that specifically inhibits porcine pancreatic elastase. J Biol Chem 278 (2003) 24986-24993
42. Sommerhoff C.P., and Schaschke N. Mast cell tryptase beta as a target in allergic inflammation: an evolving story. Curr Pharm Des 13 (2007) 313-332
43. Avrutina O., Schmoldt H.U., Gabrijelcic-Geiger D., Wentzel A., Frauendorf H., Sommerhoff C.P., Diederichsen U., and Kolmar H. Head-to-tail cyclized cystine-knot peptides by a combined recombinant and chemical route of synthesis. Chembiochem 9 (2008) 33-37
44. Souriau C., Chiche L., Irving R., and Hudson P. New binding specificities derived from Min-23, a small cystine-stabilized peptidic scaffold. Biochemistry 44 (2005) 7143-7155
45. 3 integrin by fluorescence-activated cell sorting. The engineered knottins showed minimal or no binding to other members of the integrin family. These findings demonstrate that the modification of a single loop of a cystine knot peptide can lead to biomolecules with antibody-like affinities.
46. Greenwood K.P., Daly N.L., Brown D.L., Stow J.L., and Craik D.J. The cyclic cystine knot miniprotein MCoTI-II is internalized into cells by macropinocytosis. Int J Biochem Cell Biol 39 (2007) 2252-2264. This is the first report of internalization of a macrocyclic knottin, MCoTI-II, a member of the trypsin inhibitor subfamily, into macrophage and breast cancer cells. Biotinylated MCoTI-II was shown to enter cells by macropinocytosis without trafficking to lysosomes for degradation. This indicates that this cystine knot peptide has the potential to transport grafted bioactivities to intracellular targets.
47. Avrutina O., Schmoldt H.U., Gabrijelcic-Geiger D., Le Nguyen D., Sommerhoff C.P., Diederichsen U., and Kolmar H. Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II. Biol Chem 386 (2005) 1301-1306
48. Green B.R., Catlin P., Zhang M.M., Fiedler B., Bayudan W., Morrison A., Norton R.S., Smith B.J., Yoshikami D., Olivera B.M., and Bulaj G. Conotoxins containing nonnatural backbone spacers: cladistic-based design, chemical synthesis, and improved analgesic activity. Chem Biol 14 (2007) 399-407
49. Craik D.J., Clark R.J., and Daly N.L. Potential therapeutic applications of the cyclotides and related cystine knot mini-proteins. Expert Opin Investig Drugs 16 (2007) 595-604
50. Maillere B., Mourier G., Herve M., Cotton J., Leroy S., and Menez A. Immunogenicity of a disulphide-containing neurotoxin: presentation to T-cells requires a reduction step. Toxicon 33 (1995) 475-482