The cyclotides and related macrocyclic peptides as scaffolds in drug design

Current Opinion in Drug Discovery and Development

Volumn 9, Issue 2, 2006, Pages 251-260

  Craik, David J ^a   Čemažar, Maša ^a   Daly, Norelle L ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

Circular backbone; Cyclic cystine knot; Cyclotides; Peptide engineering; Scaffold

Indexed keywords

CIRCULIN; CONOTOXIN; CUCURBITA MAXIMA TRYPSIN INHIBITOR I; CYCLOTIDE; CYCLOVIOLACIN O1; CYSTINE; ECBALLIUM ELATERIUM TRYPSIN INHIBITOR II; KALATA B1; KALATA B2; MACROCYCLIC COMPOUND; MOMORDICA COCHINCHINENSIS TRYPSIN INHIBITOR I; MOMORDICA COCHINCHINENSIS TRYPSIN INHIBITOR II; OMEGA CONOTOXIN MVIIA; SUNFLOWER TRYPSIN INHIBITOR 1; TRYPSIN INHIBITOR; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; CYCLIZATION; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG STABILITY; HEAT TOLERANCE; NONHUMAN; PROTEIN DEGRADATION; PROTEIN ENGINEERING; REVIEW; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

AMINO ACID SEQUENCE; ANIMALS; CYCLIZATION; CYCLOTIDES; CYSTINE; DRUG DESIGN; HUMANS; MOLECULAR SEQUENCE DATA; PEPTIDES; PROTEIN CONFORMATION; PROTEINS;

EID: 33645028340     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (38)

1. Craik DJ, Daly NL, Mulvenna J, Plan MR, Trabi M: Discovery, structure and biological activities of the cyclotides. Curr Protein Peptide Sci (2004) 5(5):297-315. Provides a comprehensive review listing all of the known cyclotides up to 2004 and describes the history of their discovery, together with their structures, activities and applications. This issue of the journal is dedicated to circular proteins and contains several other articles relating to cyclotides.
2. Craik DJ, Daly NL, Waine C: The cystine knot motif in toxins and implications for drug design. Toxicon (2001) 39(1):43-60.
3. Gran L, Sandberg F, Sletten K: Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine. J Ethnopharmacol (2000) 70(3):197-203. Provides a historical account of the discovery of kalata B1, the first cyclotide to be reported. At the time that its activity was found the peptide had not been structurally characterized.
4. Jennings CV, Rosengren KJ, Daly NL, Plan M, Stevens J, Scanlon MJ, Waine C, Norman DG, Anderson MA, Craik DJ: Isolation, solution structure, and insecticidal activity of kalata B2, a circular protein with a twist: Do Möbius strips exist in nature? Biochemistry (2005) 44(3):851-860.
5. Trabi M, Craik DJ: Circular proteins - no end in sight Trends Biochem Sci (2002) 27(3):132-138.
6. Craik DJ, Simonsen S, Daly NL: The cyclotides: Novel macrocyclic peptides as scaffolds in drug design. Curr Opin Drug Discovery Dev (2002) 5(2):251-260. Provides the first review on the potential pharmaceutical applications of cyclotides, and is the background review that is updated in the current article.
7. Simonsen SM, Sando L, Ireland DC, Colgrave ML, Bharathi R, Goransson U, Craik DJ: A continent of plant defense peptide diversity: Cyclotides in Australian hybanthus (Violaceae). Plant Cell (2005) 17(11):3176-3189. Describes a study that surveyed the sequence diversity of cyclotides in a single genus of the Violaceae family across the Australian continent, and led to an estimate of the likely existence of > 9000 cyclotides.
8. Mulvenna JP, Wang C, Craik DJ: CyBase: A database of cyclic protein sequence and structure. Nucleic Acids Res (2006) 34(database issue):D192-194. Introduces Cybase, the Web-based database for circular proteins, which includes cyclotides. Cybase is a repository of information about cyclic protein biology, their sequences and 3D structures.
9. Craik DJ, Daly NL, Bond T, Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol (1999) 294(5):1327-1336. The paper that coined the name 'cyclotides' for macrocyclic peptides having a CCK motif. Reports the discovery of numerous examples of such peptides in the Violaceae plant family, and the topological features of the CCK motif are also described.
10. Hernandez JF, Gagnon J, Chiche L, Nguyen TM, Andrieu JP, Heitz A, Trinh Hong T, Pham TT, Le Nguyen D: Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry (2000) 39(19):5722-5730. Describes the discovery of a new class of macrocyclic knotted proteins that were different from previously discovered cyclotides. The discovery of MCoTI-II provides a link between acyclic knottin proteins such as EETI-II and the macrocyclic cyclotides.
11. Felizmenio-Quimio ME, Daly NL, Craik DJ: Circular proteins in plants: Solution structure of a novel macrocyclic trypsin inhibitor from Momordica cochinchinensis. J Biol Chem (2001) 276(25):22875-22882.
12. Chiche L, Heitz A, Gelly JC, Gracy J, Chau PT, Ha PT, Hernandez JF, Le-Nguyen D: Squash Inhibitors: From structural motifs to macrocyclic knottlns. Curr Protein Peptide Sci (2004) 5(5):341-349. Provides a review on the squash inhibitor family, which shares the typical knottin fold. This paper introduces both the linear and macrocyclic knottins and examines their conserved structural features.
13. Christmann A, Walter K, Wentzel A, Krätzner R, Kolmar H: The cystine knot of a squash-type protease inhibitor as a structural scaffold for Escherichia coli cell surface display of conformationally constrained peptides. Protein Eng (1999) 12(9):797-806. Demonstrates that E coli cell surface display of peptides based on the EETI-II cystlne knot scaffold is an effective technique for the identification of novel peptides with high binding affinity.
14. Skjeldal L, Gran L, Sletten K, Volkman BF: Refined structure and metal binding site of the kalata B1 peptide. Arch Biochem Biophys (2002) 399(2):142-148.
15. Göransson U, Craik DJ: Disulfide mapping of the cyclotide kalata B1. Chemical proof of the cystic cystine knot motif. J Biol Chem (2003) 278(48):48188-48196. Describes a study in which the disulfide connectivity of cyclotide kalata B1 is confirmed to be consistent with a cystine knot motif by means of chemical modification and proteolytic digestion.
16. Rosengren KJ, Daly NL, Plan MR, Waine C, Craik DJ: Twists, knots and rings in proteins. Structural definition of the cyclotide framework. J Biol Chem (2003) 278(10):8606-8616. Describes a high resolution structural analysis of two prototypic cyclotides, kalata B1 and cycloviolacin O1 and defines the role of the conserved residues in the cyclotides. This paper also confirms the disulfide connectivities in these two representative cyclotides.
17. Barry DG, Daly NL, Bokesch HR, Gustafson KR, Craik DJ: Solution structure of the cyclotide palicourein: Implications for the development of a pharmaceutical framework. Structure (2004) 12(1):85-94.
18. Mulvenna JP, Sando L, Craik DJ: Processing of a 22 kDa precursor protein to produce the circular protein tricyclon A. Structure (2005) 13(5):691-701.
19. Gustafson KR, McKee TC, Bokesch HR: Anti-HIV cyclotides. Curr Protein Peptide Sci (2004) 5(5):331-340. An excellent review from one of the research groups involved in the original discovery of cyclotides, with a particular emphasis on anti-HIV activity.
20. Daly NL, Gustafson KR, Craik DJ: The role of the cyclic peptide backbone in the anti-HIV activity of the cyclotide kalata B1. FEBS Lett (2004) 574(1-3):69-72.
21. Lindholm P, Göransson U, Johansson S, Claeson P, Gulbo J, Larsson R, Bohlin L, Backlund A: Cyclotides: A novel type of cytotoxic agents. Mol Cancer Ther (2002) 1(6):365-369.
22. Daly NL, Craik DJ: Acyclic permutants of naturally occurring cyclic proteins. Characterization of cystine knot and β-sheet formation in the macrocycllc polypeptide kalata B1. J Biol Chem (2000) 276(25):19068-19075.
23. Barry DG, Daly NL, Clark RJ, Sando L, Craik DJ: Linearization of a naturally occurring circular protein maintains structure but eliminates hemolytic activity. Biochemistry (2003) 42(22):6688-6695
24. Simonsen SM, Daly NL, Craik DJ: Capped acyclic permutants of the circular protein kalata B1. FEBS Lett (2004) 577(3):399-402.
25. Chen B, Colgrave ML, Wang C, Craik DJ: Cycloviolacin H4, a hydrophobia cyclotide from Viola hederaceae. J Nat Prod (2005):69(1):23-28.
26. Colgrave ML, Craik DJ: Thermal, chemical and enzymatic stability of the cyclotide kalata B1: The importance of the cyclic cystine knot Biochemistry (2004) 43(20):5965-5975. Exemplifies the exceptional stability of the cyclotides and includes a systematic investigation of the role of the cystine knot and cyclic backbone in the biophysical properties of cyclotides.
27. Clark RJ, Daly NL, Craik DJ: Structural plasticity of the cyclic-cystine knot framework: Implications for biological activity and drug design. Biochem J (2006) 394(1):85-93.
28. Kratzner R, Debreczeni JE, Pape T, Schneider TR, Wentzel A, Kolmar H, Sheldrick GM, Uson I: Structure of Ecballium elaterium trypsin inhibitor II (EETI-II): A rigid molecular scaffold. Acta Crystallogr D Biol Crystallogr (2005) 61(Pt 9):1255-1262. Describes a study demonstrating the similarity of the 3D structures of uncomplexed wild-type EETI-II, one of its mutants and EETI-II in complex with trypsin. This paper suggests that this cystine knot framework has a high degree of rigidity, making it a suitable choice as a molecular scaffold.
29. Hilpert K, Wessner H, Schneider-Mergener J, Welfie K, Misselwitz R, Welfie H, Hocke AC, Hippenstiel S, Hohne W. Design and characterization of a hybrid miniprotein that specifically inhibits porcine pancreatic elastase. J Biol Chem (2003) 278(27):24986-24993.
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32. Korsinczky ML, Clark RJ, Craik DJ: Disulfide bond mutagenesis and the structure and function of the head-to-tall macrocyclic trypsin inhibitor SFTI-1. Biochemistry (2005) 44(4):1145-1153.
33. Jaulent AM, Leatherbarrow RJ: Design, synthesis and analysis of novel bicyclic and bifunctional protease inhibitors. Protein Eng Des Sci (2004) 17(9):681-687. Exemplifies the SFTI-1 framework as a scaffold for introducing additional biological activity, in this case chymotrypsin inhibition.
34. Jaulent AM, Brauer AB, Matthews SJ, Leatherbarrow RJ: Solution structure of a novel C(2)-symmetrical bifunctional bicyclic inhibitor based on SFTI-1. J Biomol NMR (2005) 33(1):57-62.
35. Stawikowski M, Stawikowska R, Jaskiewicz A, Zablotna E, Rolka K: Examples of peptide-peptoid hybrid serine protease inhibitors based on the trypsin inhibitor SFTI-1 with complete protease resistance at the P1-P1′ reactive site. Chembiochem (2005) 6(6):1057-1061.
36. Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ: Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the α-conotoxin MII. Proc Natl Acad Sci USA (2005) 102(39):13767-13772. Provides the first literature report on the principles and practice of cyclizing conotoxins to produce increased stability with retained biological and structural properties.
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