The emerging role of new protein scaffold-based agents for treatment of cancer

Cancer Genomics and Proteomics

Volumn 10, Issue 4, 2013, Pages 155-168

  Weidle, Ulrich H ^a   Auer, Johannes ^a   Brinkmann, Ulrich ^a   Georges, Guy ^a   Tiefenthaler, Georg ^a  

^a ROCHE INNOVATION CENTER MUNICH   (Germany)

Author keywords

Angiogenesis; Extension of plasma half life; HER signaling; multivalent; Multispecific; Phage and ribosome display; Pharmacokinetics; Randomisation of loops and sheets; Review

Indexed keywords

AFFIBODIES; AFFILIN; ANTICALIN; ARMADILLO DOMAIN PROTEIN; ATRIMER; AVIMER; CETUXIMAB; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DARPIN; ECALLANTIDE; FYNOMER; KALLIKREIN; KNOTTIN; LIPOCALIN; MONOCLONAL ANTIBODY DC101; NIMOTUZUMAB; PANITUMUMAB; PEGDINETANIB; SCAFFOLD PROTEIN; SORAFENIB; SUNITINIB; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; CANCER THERAPY; DRUG BLOOD LEVEL; DRUG HALF LIFE; IC 50; LIGAND BINDING; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PROTEIN ENGINEERING; PROTEIN SECONDARY STRUCTURE; REVIEW;

ARMADILLO;

EID: 84882339603     PISSN: 11096535     EISSN: 17906245     Source Type: Journal    
DOI: None     Document Type: Review

References (113)

1. Reichert JM: Antibody-based therapeutics to watch in 2011. MAbs 3: 76-99, 2011.
2. Nelson AL, Dhimolea E and Reichert JM: Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9: 767-774, 2010.
3. Kontermann RE: Dual targeting strategies with bispecific antibodies. mAbs 4: 182-197, 2012.
4. Kontermann, RE: Bispecific Antibodies. Springer Verlag, Berlin, pp. 115 133, 2011.
5. Weidle UH, Tiefenthaler, G, Weiss EH, Georges G and Brinkmann U: The intriguing options of multispecific antibody formats for treatment of cancer. Cancer Genomics Proteomics 10: 1-18, 2013.
6. Kontermann RE: Alternative antibody formats. Curr Opin Mol Ther 12: 176-183, 2010.
7. Fischer N and Léger O: Bispecific antibodies: Molecules that enable novel therapeutic strategies. Pathobiology 74: 3-14, 2007.
8. Saerens D, Ghassabeh GH and Muyldermans S: Single-domain antibodies as building blocks for novel therapeutics. Curr Opin Pharmacol 8: 600-608, 2008.
9. Streltsov VA, Varghese JN, Carmichael JA, Irving RA, Hudson PJ and Nuttall SD: Structural evidence for evolution of shark Ig new antigen receptor variable domain antibodies from a cell-surface receptor. Proc Natl Acad Sci USA 101: 12444-12449, 2004.
10. Segal DM, Weiner GJ and Weiner LM: Bispecific antibodies in cancer therapy. Curr Opin Immunol 11: 558-562, 1999.
11. Todorovska A, Roovers RC, Dolezal O, Kortt AA, Hoogenboom HR and Hudson PJ: Design and application of diabodies, triabodies and tetrabodies for cancer targeting. J Immunol Methods 248: 47-66, 2001.
12. Shaw AS and Filbert EL: Scaffold proteins and immune-cell signalling. Nat Rev Immunol 9: 47-56, 2009.
13. Burack WR and Shaw AS: Signal transduction: Hanging on a scaffold. Curr Opin Cell Biol 12: 211-216, 2000.
14. Gebauer M and Skerra A: Engineered protein scaffolds as next-generation antibody therapeutics. Curr Opin Chem Biol 13: 245-255, 2009.
15. Nuttall SD and Walsh RB: Display scaffolds: Protein engineering for novel therapeutics. Curr Opin Pharmacol 8: 609-615, 2008.
16. Carter PJ: Introduction to current and future protein therapeutics: a protein engineering perspective. Exp Cell Res 317: 1261-1269, 2011.
17. Binz HK, Amstutz P and Plückthun A: Engineering novel binding proteins from nonimmunoglobulin domains. Nat Biotechnol 23: 1257-1268, 2005.
18. Carter PJ: Potent antibody therapeutics by design. Nat Rev Immunol 6: 343-357, 2006.
19. Lipovsek D: Adnectins: Engineered target-binding protein therapeutics. Protein Eng Des Sel 24: 3-9, 2011.
20. Hackel BJ, Kapila A and Wittrup KD: Picomolar affinity fibronectin domains engineered utilizing loop length diversity, recursive mutagenesis, and loop shuffling. J Mol Biol 381: 1238-1252, 2008.
21. Koldobskaya Y, Duguid EM, Shechner DM, Suslov NB, Ye J, Sidhu SS, Bartel DP, Koide S, Kossiakoff AA and Piccirilli JA: A portable RNA sequence whose recognition by a synthetic antibody facilitates structural determination. Nat Struct Mol Biol 18: 100-106, 2011.
22. Xu L, Aha P, Gu K, Kuimelis RG, Kurz M, Lam T, Lim AC, Liu H, Lohse PA, Sun L, Weng S, Wagner RW and Lipovsek D: Directed evolution of high-affinity antibody mimics using mRNA display. Chem Biol 9: 933-942, 2002.
23. Ramamurthy V, Krystek SR Jr, Bush A, Wei A, Emanuel SL, Das Gupta R, Janjua A, Cheng L, Murdock M, Abramczyk B, Cohen D, Lin Z, Morin P, Davis JH, Dabritz M, McLaughlin DC, Russo KA, Chao G, Wright MC, Jenny VA, Engle LJ, Furfine E and Sheriff S: Structures of adnectin/protein complexes reveal an expanded binding footprint. Structure 20: 259-269, 2012.
24. Mamluk R, Carvajal IM, Morse BA, Wong H, Abramowitz J, Aslanian S, Lim AC, Gokemeijer J, Storek MJ, Lee J, Gosselin M, Wright MC, Camphausen RT, Wang J, Chen Y, Miller K, Sanders K, Short S, Sperinde J, Prasad G, Williams S, Kerbel R, Ebos J, Mutsaers A, Mendlein JD, Harris AS and Furfine ES: Antitumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. MAbs 2: 199-208, 2010.
25. Ackermann M, Carvajal IM, Morse BA, Moreta M, O'Neil S, Kossodo S, Peterson JD, Delventhal V, Marsh HN, Furfine ES and Konerding MA: Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts. Int J Oncol 38: 71-80, 2011.
26. Dineen SP, Sullivan LA, Beck AW, Miller AF, Carbon JG, Mamluk R, Wong H and Brekken RA: The adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer. BMC Cancer 8: 352, 2008.
27. Tolcher AW, Sweeney CJ, Papadopoulos K, Patnaik A, Chiorean EG, Mita AC, Sankhala K, Furfine E, Gokemeijer J, Iacono L, Eaton C, Silver BA and Mita M: Phase I and pharmacokinetic study of CT-322 (BMS-844203), a targeted adnectin inhibitor of VEGFR-2 based on a domain of human fibronectin. Clin Cancer Res 17: 363-371, 2011.
28. Emanuel SL, Engle LJ, Chao G, Zhu RR, Cao C, Lin Z, Yamniuk AP, Hosbach J, Brown J, Fitzpatrick E, Gokemeijer J, Morin P, Morse BA, Carvajal IM, Fabrizio D, Wright MC, Das Gupta R, Gosselin M, Cataldo D, Ryseck RP, Doyle ML, Wong TW, Camphausen RT, Cload ST, Marsh HN, Gottardis MM and Furfine ES: A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor. MAbs 3: 38-48, 2011.
29. Skerra A: Alternative binding proteins: Anticalins-harnessing the structural plasticity of the lipocalin ligand pocket to engineer novel binding activities. FEBS J 275: 2677-2683, 2008.
30. Skerra A: Anticalins as alternative binding proteins for therapeutic use. Curr Opin Mol Ther 9: 336-344, 2007.
31. Gebauer M and Skerra A: Engineered protein scaffolds as next-generation antibody therapeutics. Curr Opin Chem Biol 13: 245-255, 2009.
32. Gebauer M and Skerra A: Anticalins, small engineered binding proteins based on the lipocalin scaffold. Methods Enzymol 503: 157-188, 2012.
33. Schlehuber S and Skerra A: Duocalins: Engineered ligand-binding proteins with dual specificity derived from the lipocalin fold. Biol Chem 382: 1335-1342, 2001.
34. Leach DR, Krummel MF and Allison JP: Enhancement of antitumor immunity by CTLA4 blockade. Science 271: 1734-1736, 1996.
35. Schönfeld D, Matschiner G, Chatwell L, Trentmann S, Gille H, Hülsmeyer M, Brown N, Kaye PM, Schlehuber S, Hohlbaum AM and Skerra A: An engineered lipocalin specific for CTLA4 reveals a combining site with structural and conformational features similar to antibodies. Proc Natl Acad Sci USA 106: 8198-8203, 2009.
36. Hohlbaum AM and Skerra A: Anticalins: the lipocalin family as a novel protein scaffold for the development of next-generation immunotherapies. Expert Rev Clin Immunol 3: 491-501, 2007.
37. Bode W and Huber R: Natural protein proteinase inhibitors and their interaction with proteinases. Eur J Biochem 204: 433-451, 1992.
38. Hosse RJ, Rothe A and Power BE: A new generation of protein display scaffolds for molecular recognition. Protein Sci 15: 14-27, 2006.
39. Lehmann A: Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther 8: 1187-1199, 2008.
40. Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, Horn PT and Pullman WE: Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 363: 523-531, 2010.
41. Gliemann J: Receptors of the low-density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands. Biol Chem 379: 951-964, 1998.
42. Krieger M and Herz J: Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 63: 601-637, 1994.
43. North CL and Blacklow SC: Structural independence of ligand-binding modules five and six of the LDL receptor. Biochemistry 38: 3926-3935, 1999.
44. Huang W, Dolmer K and Gettins PG: NMR solution structure of complement-like repeat CR8 from the low-density lipoprotein receptor-related protein. J Biol Chem 274: 14130-14136, 1999.
45. Silverman J, Liu Q, Bakker A, To W, Duguay A, Alba BM, Smith R, Rivas A, Li P, Le H, Whitehorn E, Moore KW, Swimmer C, Perlroth V, Vogt M, Kolkman J and Stemmer WP: Bivalent avimer proteins evolved by exon shuffling of a family of human receptor domains. Nat Biotechnol 23: 1556-1561, 2005.
46. Kolmar H: Natural and engineered cystine knot miniproteins for diagnostic and therapeutic applications. Curr Pharm Des 17: 4329-4336, 2011.
47. Kolmar H and Skerra A: Alternative binding proteins get mature: Rivalling antibodies. FEBS J 275: 2667, 2008.
48. Gracy J and Chiche L: Structure and modeling of knottins, a promising molecular scaffold for drug discovery. Curr Pharm Des 17: 4337-4350, 2011.
49. Gracy J, Le-Nguyen D, Gelly JC, Kaas Q, Heitz A and Chiche L: KNOTTIN: The knottin or inhibitor cystine knot scaffold in 2007. Nucleic Acids Res 36: 314-319, 2008.
50. Gunasekera S, Foley FM, Clark RJ, Sando L, Fabri LJ, Craik DJ and Daly NL: Checking stabilized vascular endothelial growth factor-A antagonists: Synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J Med Chem 51: 7697-7704, 2008.
51. Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, Davis AM, Tansik RL, Mattheakis LC, Boytos CM, Schatz PJ, Baccanari DP, Wrighton NC, Barrett RW and Dower WJ: Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 276: 1696-1699, 1997.
52. Silverman AP, Levin AM, Lahti JL and Cochran JR: Engineered cystine-knot peptides that bind alpha(v)beta(3) integrin with antibody-like affinities. J Mol Biol 385: 1064-1075, 2009.
53. Kimura RH, Cheng Z, Gambhir SS and Cochran JR: Engineered knottin peptides: A new class of agents for imaging integrin expression in living subjects. Cancer Res 69: 2435-2442, 2009.
54. Kolmar H: Biological diversity and therapeutic potential of natural and engineered cystine knot miniproteins. Curr Opin Pharmacol 9: 608-614, 2009.
55. Cooke MP and Perlmutter RM: Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol 1: 66-74, 1989.
56. Katagiri T, Urakawa K, Yamanashi Y, Semba K, Takahashi T, Toyoshima K, Yamamoto T and Kano K: Overexpression of src family gene for tyrosine-kinase p59fyn in CD4-CD8-T-cells of mice with a lymphoproliferative disorder. Proc Natl Acad Sci USA 86: 10064-10068, 1989.
57. Kawakami T, Pennington CY and Robbins KC: Isolation and oncogenic potential of a novel human src-like gene. Mol Cell Biol 6: 4195-4201, 1986.
58. Ren R, Mayer BJ, Cicchetti P and Baltimore D: Identification of a ten-amino acid proline-rich SH3 binding site. Science 259: 1157-1161, 1993.
59. Bertschinger J and Neri D: Covalent DNA display as a novel tool for directed evolution of proteins in vitro. Protein Eng Des Sel 17: 699-707, 2004.
60. Bertschinger J, Grabulovski D and Neri D: Selection of single domain binding proteins by covalent DNA display. Protein Eng Des Sel 20: 57-68, 2007.
61. Castellani P, Viale G, Dorcaratto A, Nicolo G, Kaczmarek J, Querze G and Zardi L: The fibronectin isoform containing the ED-B oncofetal domain: A marker of angiogenesis. Int J Cancer 59: 612-618, 1994.
62. Grabulovski D, Kaspar M and Neri D: A novel, non-immunogenic FYN SH3-derived binding protein with tumor vascular-targeting properties. J Biol Chem 282: 3196-3204, 2007.
63. Pasche N and Neri D: Immunocytokines: A novel class of potent armed antibodies. Drug Discov Today 17: 583-590, 2012
64. Clemmensen I, Petersen LC and Kluft C: Purification and characterization of a novel, oligomeric, plasminogen kringle 4-binding protein from human plasma: Tetranectin. Eur J Biochem 156: 327-333, 1986.
65. Fuhlendorff J, Clemmensen I and Magnusson S: Primary structure of tetranectin, a plasminogen kringle 4-binding plasma protein: homology with asialoglycoprotein receptors and cartilage proteoglycan core protein. Biochemistry 26: 6757-6764, 1987.
66. Nielsen BB, Kastrup JS, Rasmussen H, Holtet TL, Graversen JH, Etzerodt M, Thøgersen HC and Larsen IK: Crystal structure of tetranectin, a trimeric plasminogen-binding protein with an alpha-helical coiled coil. FEBS Lett 412: 388-396, 1997.
67. Zelensky AN and Gready JE: The C-type lectin-like domain superfamily. FEBS J 272: 6179-6217, 2005.
68. Holtet TL, Graversen JH, Clemmensen I, Thøgersen HC and Etzerodt M: Tetranectin, a trimeric plasminogen-binding C-type lectin. Protein Sci 6: 1511-1515, 1997.
69. Byla P, Andersen MH, Holtet TL, Jacobsen H, Munch M, Gad HH, Thøgersen HC and Hartmann R: Selection of a novel and highly specific tumor necrosis factor alpha (TNFα) antagonist: Insight from the crystal structure of the antagonist-TNFα complex. J Biol Chem 285: 12096-12100, 2010.
70. Rohn J: Newsmaker: Anaphore. Nat Biotechnol 28: 1143, 2010.
71. Waterhouse P, Marengère LE, Mittrücker HW and Mak TW: CTLA4, a negative regulator of T-lymphocyte activation. Immunol Rev 153: 183-207, 1996.
72. Lauwereys M, Arbabi Ghahroudi M, Desmyter A, Kinne J, Hölzer W, De Genst E, Wyns L and Muyldermans S: Potent enzyme inhibitors derived from dromedary heavy-chain antibodies. EMBO J 17: 3512-3520, 1998.
73. Roux KH, Greenberg AS, Greene L, Strelets L, Avila D, McKinney EC and Flajnik MF: Structural analysis of the nurse shark (new) antigen receptor (NAR): Molecular convergence of NAR and unusual mammalian immunoglobulins. Proc Natl Acad Sci USA 95: 11804-11809, 1998.
74. Linsley PS, Nadler SG, Bajorath J, Peach R, Leung HT, Rogers J, Bradshaw J, Stebbins M, Leytze G, Brady W, Malacko AR, Marquardt H and Shaw SY: Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA4). A disulfide-linked homodimer binds two CD86 molecules. J Biol Chem 270: 15417-15424, 1995.
75. Nuttall SD, Rousch MJ, Irving RA, Hufton SE, Hoogenboom HR and Hudson PJ: Design and expression of soluble CTLA4 variable domain as a scaffold for the display of functional polypeptides. Proteins 36: 217-227, 1999.
76. Hufton SE, Van Neer N, Van Den Beuken T, Desmet J, Sablon E and Hoogenboom HR: Development and application of cytotoxic T-lymphocyte-associated antigen 4 as a protein scaffold for the generation of novel binding ligands. FEBS Lett 475: 225-231, 2000.
77. Grönwall C and Ståhl S: Engineered affinity proteins generation and applications. J Biotechnol 140: 254-269, 2009.
78. Boersma YL and Plückthun A: DARPins and other repeat protein scaffolds: Advances in engineering and applications. Curr Opin Biotechnol 22: 849-857, 2011.
79. Stumpp MT, Binz HK and Amstutz P: DARPins: A new generation of protein therapeutics. Drug Discov Today 13: 695-701, 2008.
80. Stumpp MT and Amstutz P: DARPins: A true alternative to antibodies. Curr Opin Drug Discov Devel 10: 153-159, 2007.
81. Zahnd C, Amstutz P and Plückthun A: Ribosome display: Selecting and evolving proteins in vitro that specifically bind to a target. Nat Methods 4: 269-279, 2007.
82. Eggel A, Baumann MJ, Amstutz P, Stadler BM and Vogel M: DARPins as bispecific receptor antagonists analyzed for immuno-globulin E receptor blockage. J Mol Biol 393: 598-607, 2009.
83. Martin-Killias P, Stefan N, Rothschild S, Plückthun A and Zangemeister-Wittke U: A novel fusion toxin derived from an EpCAM-specific designed ankyrin repeat protein has potent antitumor activity. Clin Cancer Res 17: 100-110, 2011.
84. Zahnd C, Wyler E, Schwenk JM, Steiner D, Lawrence MC, McKern NM, Pecorari F, Ward CW, Joos TO and Plückthun A: A designed ankyrin repeat protein evolved to picomolar affinity to Her2. J Mol Biol 369: 1015-1028, 2007.
85. Dreier B, Mikheeva G, Belousova N, Parizek P, Boczek E, Jelesarov I, Forrer P, Plückthun A and Krasnykh V: Her2-specific multivalent adapters confer designed tropism to adenovirus for gene targeting. J Mol Biol 405: 410-426, 2011.
86. Stahl A, Stumpp MT, Schlegel A, Ekawardhani S, Lehrling C, Martin G, Gulotti-Georgieva M, Villemagne D, Forrer P, Agostini HTand Binz HK: Highly potent VEGF-A-antagonistic DARPins as anti-angiogenic agents for topical and intravitreal applications. Angiogenesis 16: 101-111, 2013.
87. Nygren PA: Alternative binding proteins: Affibody binding proteins developed from a small three-helix bundle scaffold. FEBS J 275: 2668-2676, 2008.
88. Nilsson FY and Tolmachev V: Check molecules: New protein domains for molecular imaging and targeted tumor therapy. Curr Opin Drug Discov Devel 10: 167-175, 2007.
89. Friedman M, Nordberg E, Höidén-Guthenberg I, Brismar H, Adams GP, Nilsson FY, Carlsson J and Ståhl S: Phage display selection of affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor. Protein Eng Des Sel 20: 189-199, 2007.
90. Tolmachev V, Orlova A, Pehrson R, Galli J, Baastrup B, Andersson K, Sandström M, Rosik D, Carlsson J, Lundqvist H, Wennborg A and Nilsson FY: Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific affibody molecule. Cancer Res 67: 2773-2782, 2007.
91. Friedman M, Lindström S, Ekerljung L, Andersson-Svahn H, Carlsson J, Brismar H, Gedda L, Frejd FY and Ståhl S: Engineering and characterization of a bispecific HER2 × EGFR-binding affibody molecule. Biotechnol Appl Biochem 54: 121-131, 2009.
92. Zielinski R, Lyakhov I, Jacobs A, Chertov O, Kramer-Marek G, Francella N, Stephen A, Fisher R, Blumenthal R and Capala J: Affitoxin-a novel recombinant, HER2-specific, anticancer agent for targeted therapy of HER2-positive tumors. J Immunother 32: 817-825, 2009.
93. Zielinski R, Lyakhov I, Hassan M, Kuban M, Shafer-Weaver K, Gandjbakhche A and Capala J: HER2-affitoxin: A potent therapeutic agent for the treatment of HER2-overexpressing tumors. Clin Cancer Res 17: 5071-5081, 2011.
94. Capala J and Bouchelouche K: Molecular imaging of HER2-positive breast cancer: A step toward an individualized 'image and treat' strategy. Curr Opin Oncol 22: 559-566, 2010.
95. Löfblom J, Feldwisch J, Tolmachev V, Carlsson J, Ståhl S and Frejd FY: Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett 584: 2670-2680, 2010.
96. Tolmachev V: Imaging of HER-2 overexpression in tumors for guiding therapy. Curr Pharm Des 14: 2999-3019, 2008.
97. Jaenicke R and Slingsby C: Lens crystallins and their microbial homologs: Structure, stability, and function. Crit Rev Biochem Mol Biol 36: 435-499, 2001.
98. Fu QS, Song AX and Hu HY: Structural aspects of ubiquitin binding specificities. Curr Protein Pept Sci 13: 482-489, 2012.
99. Hey T, Fiedler E, Rudolph R and Fiedler M: Artificial, non-antibody binding proteins for pharmaceutical and industrial application. Trends Biotechnol 10: 514-522, 2005.
100. Ebersbach H, Fiedler E, Scheuermann T, Fiedler M, Stubbs MT, Reimann C, Proetzel G, Rudolph R and Fiedler U: Affilin-novel binding molecules based on human gamma-B-crystallin, an all beta-sheet protein. J Mol Biol 372: 172-185, 2007.
101. Hoffmann A, Kovermann M, Lilie H, Fiedler M, Balbach J, Rudolph R and Pfeifer S: New binding mode of TNF-α revealed by ubiquitin-based binding protein. PLoS ONE e31298, 2012.
102. Perrimon N and Mahowald AP: Multiple functions of segment polarity genes in Drosophila. Dev Biol 119: 587-600, 1987.
103. Wieschaus E and Riggleman R: Autonomous requirements for the segment polarity gene armadillo during Drosophila embryogenesis. Cell 49: 177-184, 1987.
104. Andrade MA, Petosa C, O'Donoghue SI, Müller CW and Bork P: Comparison of ARM and HEAT protein repeats. J Mol Biol 309: 1-18, 2001.
105. Hatzfeld M: The armadillo family of structural proteins. Int Rev Cytol 186: 179-224, 1999.
106. Tewari R, Bailes E, Bunting KA and Coates JC: Armadillo-repeat protein functions: Questions for little creatures. Trends Cell Biol 20: 470-481, 2010.
107. Parmeggiani F, Pellarin R, Larsen AP, Varadamsetty G, Stumpp MT, Zerbe O, Caflisch A and Plückthun A: Designed armadillo repeat proteins as general peptide-binding scaffolds: Consensus design and computational optimization of the hydrophobic core. J Mol Biol 376: 1282-1304, 2008.
108. Varadamsetty G, Tremmel D, Hansen S, Parmeggiani F and Plückthun A: Designed armadillo repeat proteins: Library generation, characterization and selection of peptide binders with high specificity. J Mol Biol 424: 68-87, 2012.
109. Madhurantakam C, Varadamsetty G, Grütter MG, Plückthun A and Mittl PR: Structure-based optimization of designed armadillo-repeat proteins. Protein Sci 21: 1015-2108, 2012.
110. Alfarano P, Varadamsetty G, Ewald C, Parmeggiani F, Pellarin R, Zerbe O, Plückthun A and Caflisch A: Optimization of designed armadillo repeat proteins by molecular dynamics simulations and NMR spectroscopy. Protein Sci 21: 1298-1314, 2012.
111. Skerra A: Engineered protein scaffolds for molecular recognition. J Mol Recognit 13: 167-187, 2000.
112. Berman HM, Westbrook J, Feng Z, Gilliland G, Bjat TN, Weissig H, Shindyalov IN and Bourne PE: The Protein Data Bank (www.pdb.org). Nucleic Acids Res 28: 235-242, 2000.
113. Accelrys Software Inc., Discovery Studio Modeling Environment, Release 3.1, San Diego: Accelrys Software Inc., 2007.