Cyclotides. Prospects for using violet oxytocin-like substances to create a new generation of pharmacological agents

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Abstract

This review article focuses on the use of violets and their derivatives as medicinal agents. Special attention is given to the historical aspects of using the healing properties of violets, as well as the analysis of substances derived from these plants for pharmaceutical production. The article specifically discusses oxytocin-like substances found in violets, particularly cyclotides. Cyclotides are globular microproteins with a unique head-to-tail cyclized backbone stabilized by three disulfide bonds forming a cystine knot. The chemical characteristics of cyclotides make them suitable for use as recombinant scaffolds in the design and development of ligands for G protein-coupled receptors, which are part of the modern generation of drugs. The development of ligands for bradykinin and κ-opioid receptors, which are in demand in modern pharmacology, is described in detail.

About the authors

Sergei N. Proshin

Herzen Russian State Pedagogical University

Author for correspondence.
Email: psnjsn@rambler.ru
ORCID iD: 0000-0001-9720-4381
SPIN-code: 2978-4545

Dr. Sci. (Medicine)

Russian Federation, St. Petersburg

Vladimir V. Grishin

Lesgaft National State University of Physical Education, Sports and Health; Academician I.P. Pavlov First St. Petersburg State Medical University

Email: w.grischin@yandex.ru
ORCID iD: 0000-0002-3759-8611
SPIN-code: 3452-7882
Russian Federation, Saint Petersburg; Saint Petersburg

Alina Ashotovna Dedyan

Saint Petersburg State Pediatric Medical University

Email: cute.alina.dedyan@yandex.ru
Russian Federation, Saint Petersburg

References

  1. Bubenchikov RA, Drozdova IL. Flavonoids of Violet tricolor. Farmatsiya. 2004;(2):11–12. (In Russ.)
  2. Lovkova MYa, Rabinovich AM, Ponomareva SM, et al. Why plants heal. Moscow: Nauka; 1989. 256 p. (In Russ.)
  3. Martynov АМ, Dargaeva ТD. Phenol compounds and water-soluble polysaccharides of Viola Patrinii ging. Siberian medical journal (Irkutsk). 2009;90(7):216–218. EDN: KXTJDP
  4. Martynov AM, Chuparina EV. Composition of polysaccharide complexes, macro- and microelements in Viola uniflora (Violaceae). Rastitelnye resursy. 2009;45(4):67–73. EDN: OIQQNH
  5. Martynov AM, Sobenin AM. Phenol connections and amino acids viola Langsdorffii (Fischer ex ging.). Problems of biological, medical and pharmaceutical chemistry. 2008;(4):37–39. EDN: KAJTDD
  6. Martynov AM, Chuparina EV, Dargaeva TD, Saybel OL. Investigation of phenol compounds and element composition herba Viola biflora L., growing in east Siberia. Problems of biological, medical and pharmaceutical chemistry. 2009;(4):58–60. EDN: LACTUH
  7. Palov M. Encyclopedia of medicinal plants. Transl. from Germ. M. Pavlov. Moscow: Mir; 1998. 467 p. (In Russ.)
  8. Radzinsky VE. Medicinal plants in obstetrics and gyneco¬logy. Moscow: Eksmo; 2008. 320 p. (In Russ.)
  9. Sokolov PD, editor. Plant resources of the USSR: Flowering plants, their chemical composition and use: The families Paeoniaceae – Thymelaeaceae. Leningrad: Nauka; 1986. P. 20–29. (In Russ.)
  10. Sokolov SYa. Phytotherapy and phytopharmacology.Moscow: MIA; 2000. 976 p. (In Russ.)
  11. Budantsev AL, editor. Plant resources of Russia and neighboring countries: Flowering plants, their chemical composition and utilization. Ch. II. Supplement to 1–7 vol. Saint Petersburg; 1996.P. 157–157. (In Russ.)
  12. Abecasis GR, Auton A, Brooks LD, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65. doi: 10.1038/nature11632
  13. Abdul Ghani H, Henriques ST, Huang YH, et al. Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies. Biopolymers. 2017;108(1):e22927. doi: 10.1002/bip.22927
  14. Aboye TL, Clark RJ, Burman R, et al. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides. Antioxid Redox Signal. 2011;14(1):77–86. doi: 10.1089/ars.2010.3112
  15. Arnison PG, Bibb MJ, Bierbaum G, et al. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature.Nat Prod Rep. 2013;30(1):108–112. doi: 10.1039/c2np20085f
  16. Aslam L, Kaur R, Sharma V, et al. Isolation and characterization of cyclotides from the leaves of Viola odorata L. using peptidomic and bioinformatic approach. Biotech. 2021;11(5):211.doi: 10.1007/s13205-021-02763-2
  17. Borra R, Camarero JA. Recombinant expression of backbone-cyclized polypeptides. Biopolymers. 2013;100(5):502–509.doi: 10.1002/bip.22306
  18. Calixto JB, Medeiros R, Fernandes ES, et al. Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol. 2004;143(7):803–819. doi: 10.1038/sj.bjp.0706012
  19. Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363(15):532–537. doi: 10.1056/NEJMx100067
  20. Cemazar M, Daly NL, Häggblad S, et al. Knots in rings.The circular knotted protein Momordica cochinchinensis trypsin inhibitor-II folds via a stable two-disulfide intermediate. J Biol Chem. 2006;281(12):8224–8232. doi: 10.1074/jbc.M513399200
  21. Chaudhuri D, Aboye T, Camarero JA. Using backbone-cyclized Cys-rich polypeptides as molecular scaffolds to target protein-protein interactions. Biochem J. 2019;476(1):67–83. doi: 10.1042/BCJ20180792
  22. Chen B, Colgrave ML, Wang C, Craik DJ. Cycloviolacin H4, a hydrophobic cyclotide from Viola hederaceae. J Nat Prod. 2006;69(1): 23–28. doi: 10.1021/np050317i
  23. Claeson P, Goransson U, Johansson S, et al. Fractionation protocol for the isolation of polypeptides from plant biomass. J Nat Prod. 1998;61(1):77–81. doi: 10.1021/np970342r
  24. 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. doi: 10.1021/bi049711q
  25. Conlan BF, Anderson MA. Circular micro-proteins and mechanisms of cyclization. Curr Pharm Des. 2011;17(38):4318–4328. doi: 10.2174/138161211798999410
  26. Conlan BF, Gillon AD, Barbeta BL, Anderson MA. Subcellular targeting and biosynthesis of cyclotides in plant cells. Am J Bot. 2011;98(12):2018–2025. doi: 10.3732/ajb.1100382
  27. Conlan BF, Gillon AD, Craik DJ, Anderson MA. Circular proteins and mechanisms of cyclization. Biopolymers. 2010;94(5):573–583. doi: 10.1002/bip.21422
  28. Conzelmann C, Muratspahić E, Tomašević N, et al. In vitro inhibition of HIV-1 by cyclotide-enriched extracts of Viola tricolor.Front Pharmacol. 2022;13:888961. doi: 10.3389/fphar.2022.888961
  29. Craik DJ. Circling the enemy: cyclic proteins in plant defence. Trends Plant Sci. 2009;14(6):328–334.doi: 10.1016/j.tplants.2009.03.003
  30. Craik DJ, Lee M-H, Rehm FBH, et al. Ribosomally-synthesised cyclic peptides from plants as drug leads and pharmaceutical scaffolds. Bioorg Med Chem. 2018;26(10):2727–2735.doi: 10.1016/j.bmc.2017.08.005
  31. 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):1327–1331.doi: 10.1006/jmbi.1999.3383
  32. Dang TT, Chan LY, Huang Y-H, et al. Exploring the sequence diversity of cyclotides from Vietnamese Viola species. J Nat Prod. 2020;83(6):1817–1828. doi: 10.1021/acs.jnatprod.9b01218
  33. Davenport AP, Scully CCG, Graaf de C, et al. Advances in therapeutic peptides targeting G protein-coupled receptors. Nat Rev Drug Discov. 2020;19:389–413. doi: 10.1038/s41573-020-0062-z
  34. Dawson PE, Muir TW, Clark-Lewis I, Kent SB. Synthesis of proteins by native chemical ligation. Science. 1994;266(5186): 776–779. doi: 10.1126/science.7973629
  35. Dutton JL, Renda RF, Waine C, et al. Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteins. J Biol Chem. 2004;279(45):46858–4667.doi: 10.1074/jbc.M407421200
  36. Eichel K, Zastrow von M. Subcellular organization of GPCR signaling. Trends Pharmacol Sci. 2018;39(2):200–212.doi: 10.1016/j.tips.2017.11.009
  37. 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):22875–22881. doi: 10.1074/jbc.M101666200
  38. Gorman M, Neuss N, Svoboda GH, et al. A note on the alkaloids of Vinca rosea Linn. (Catharanthus roseus G. Don.). II. Catharanthine, lochnericine, vindolinine, and vindoline. J Am Pharm Assoc. 1959;48(4):256–259. doi: 10.1002/jps.3030480419
  39. Gould A, Camarero JA. Cyclotides: Overview and biotechnological applications. ChemBioChem. 2017;18(14):1350–1363.doi: 10.1002/cbic.201700153
  40. Grage SL, Sani MA, Cheneval O, et al. Orientation and location of the cyclotide Kalata B1 in lipid bilayers revealed by solid-state NMR. Biophys J. 2017;112(4):630–642. doi: 10.1016/j.bpj.2016.12.040
  41. Gran L. Oxytocic principles of Oldenlandia affinis. Lloydia. 1973;36(2):174–181.
  42. Gran L. On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol Toxicol (Copenh). 1973;33(5):400–408.doi: 10.1111/j.1600-0773.1973.tb01541.x
  43. Gran L, Sandberg F, Sletten KJ. Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine. Ethnopharmacol. 2000;70(3):197–203.doi: 10.1016/s0378-8741(99)00175-0
  44. Gransson U, Luijendijk T, Johansson S, et al. Seven novel macrocyclic polypeptides from Viola arvensis. J Nat Prod. 1999;62(2):283–286. doi: 10.1021/np9803878
  45. Gruber CW, Cemazar M, Clark RJ, et al. A novel plant protein-disulfide isomerase involved in the oxidative folding of cystine knot defense proteins. J Biol Chem. 2007;282(28):20435–20442. doi: 10.1074/jbc.M700018200
  46. Gruber CW, Elliott AG, Ireland DC, et al. Distribution and evolution of circular miniproteins in flowering plants. Plant Cell. 2008;20(9):2471–2483. doi: 10.1105/tpc.108.062331
  47. Gupta A, Gomes I, Bobeck EN, et al. Collybolide is a novel biased agonist of kappa-opioid receptors with potent antipruritic activity. PNAS USA. 2016;113(21):6041–6047. doi: 10.1073/pnas.1521825113
  48. Harris KS, Durek T, Kaas Q, et al. Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase. Nat Commun. 2015;6:10199. doi: 10.1038/ncomms10199
  49. Hashempour H, Koehbach J, Daly NL, et al. Characterizing circular peptides in mixtures: sequence fragment assembly of cyclotides from a violet plant by MALDI-TOF/TOF mass spectrometry. Amino Acids. 2013;44(2):581–595.doi: 10.1007/s00726-012-1376-x
  50. Hauser AS, Attwood MM, Rask-Andersen M, et al. Trends in GPCR drug discovery new agents, targets and indications. Nat Rev Drug Discov. 2017;16:829–834. doi: 10.1038/nrd.2017.178
  51. Hellinger R, Koehbach J, Soltis DE, et al. Peptidomics of circular cysteine-rich plant peptides: analysis of the diversity of cyclotides from Viola tricolor by transcriptome and proteome mining. J Proteome Res. 2015;14(11):4851–4857.doi: 10.1021/acs.jproteome.5b00681
  52. Hemu X, Zhang X, Bi X, et al. Butelase 1-mediated ligation of peptides and proteins. In: Nuijens T, Schmidt M, editors. Enzyme-mediated ligation methods. Methods in molecular biology. Vol. 2012. New York: Humana, 2019. P. 83–109. doi: 10.1007/978-1-4939-9546-2_6
  53. Heitz A, Hernandez J-F, Gagnon J, et al. Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins. Biochemistry. 2001;40(27):7973–7981. doi: 10.1021/bi0106639
  54. Hilger D, Masureel M, Kobilka BK. Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol. 2018;25:4–12. doi: 10.1038/s41594-017-0011-7
  55. Huang Y-H, Du Q, Craik DJ. Cyclotides: Disulfide-rich peptide toxins in plants. Toxicon. 2019;172:33–38. doi: 10.1016/j.toxicon.2019.10.244
  56. Huang H, Player MR. Bradykinin B1 receptor antagonists as potential therapeutic agents for pain. J Med Chem. 2010;53(15):5383–5386. doi: 10.1021/jm1000776
  57. Jacob B, Vogelaar A, Cadenas E, Camarero JA. Using the cyclotide scaffold for targeting biomolecular interactions in drug development. Molecules. 2022;27(19):6430. doi: 10.3390/molecules27196430
  58. Jia X, Kwon S, Wang CA, et al. Semienzymatic cyclization of disulfide-rich peptides using Sortase A. J Biol Chem. 2014;289(10):6627–6638. doi: 10.1074/jbc.M113.539262
  59. Jin A-H, Muttenthaler M, Dutertre S, et al. Conotoxins: chemistry and biology. Chem Rev.2019;119(21):11510–11516.doi: 10.1021/acs.chemrev.9b00207
  60. Katoh T, Goto Y, Reza MS, Suga H. Ribosomal synthesis of backbone macrocyclic peptides. Chem Commun (Camb). 2011;47(36):9946–9958. doi: 10.1039/c1cc12647d
  61. Khoshkam Z, Zarrabi M, Sepehrizadeh Z, et al. Reporting a transcript from Iranian Viola tricolor, which may encode a novel cyclotide-like precursor: Molecular and in silico studies. Comput Biol Chem. 2020;84:107168. doi: 10.1016/j.compbiolchem.2019.107168
  62. Kintzing JR, Cochran JR. Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles. Curr Opin Chem Biol. 2016;34:143–150. doi: 10.1016/j.cbpa.2016.08.022
  63. Kuduk SD, Bock MG. Bradykinin B1 receptor antagonists as novel analgesics: a retrospective of selected medicinal chemistry developments. Curr Top Med Chem. 2008;8(16):1420–1430. doi: 10.2174/156802608786264263
  64. Kuroda Y, Nicacio KJ, da Silva-Jr IA, et al. Isolation, synthesis and bioactivity studies of phomactin terpenoids. Nat Chem. 2018;10:938–941. doi: 10.1038/s41557-018-0084-x
  65. Lage K. Protein–protein interactions and genetic diseases: The interactome. Biochim Biophys Acta – Mol Basis Dis. 2014;1842(10):1971–1980. doi: 10.1016/j.bbadis.2014.05.028
  66. Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26(10):2700–2711. doi: 10.1016/j.bmc.2017.06.052
  67. Marglin A, Merrifield RB. Chemical synthesis of peptides and proteins. Annu Rev Biochem. 1970;39:841–866.doi: 10.1146/annurev.bi.39.070170.004205
  68. McGregor DP. Discovering and improving novel peptide therapeutics. Curr Opin Pharmacol. 2008;8(5):616–619.doi: 10.1016/j.coph.2008.06.002
  69. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019;123(2):e273–e283. doi: 10.1016/j.bja.2019.03.023
  70. Muratspahic´ E, Freissmuth M, Gruber CW. Nature-derived peptides: a growing niche for GPCR ligand discovery. Trends Pharmacol Sci. 2019;40(5):309–312. doi: 10.1016/j.tips.2019.03.004
  71. Mylne JS, Wang CK, van der Weerden NL, Craik DJ. Cyclotides are a component of the innate defense of Oldenlandia affinis.Biopolymers. 2010;94(5):635–646. doi: 10.1002/bip.21419
  72. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–632. doi: 10.1021/acs.jnatprod.5b01055
  73. Nguyen GK, Lian Y, Pang EWH, et al. Discovery of linear cyclotides in monocot plant Panicum laxum of Poaceae family provides new insights into evolution and distribution of cyclotides in plants. J Biol Chem. 2013;288(5):3370–3380. doi: 10.1074/jbc.M112.415356
  74. Nguyen GKT, Wang S, Qiu Y, et al. Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis. Nat Chem Biol. 2014;10(9):732–738. doi: 10.1038/nchembio.1586
  75. Pelegrini PB, Quirino BF, Franco OL. Plant cyclotides: an unusual class of defense compounds. Peptides. 2007;28(7): 1475–1481. doi: 10.1016/j.peptides.2007.04.025
  76. Plückthun A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu Rev Pharmacol Toxicol. 2015;55:489–511. doi: 10.1146/annurev-pharmtox-010611-134654
  77. Pestana-Calsa MC, Ribeiro ILAC, Calsa TJr. Bioinformatics-coupled molecular approaches for unravelling potential antimicrobial peptides coding genes in Brazilian native and crop plant species. Curr Protein Pept Sci. 2010;11(3):199–209. doi: 10.2174/138920310791112138
  78. Plan MR, Saska I, Cagauan AG, Craik DJ. Backbone cyclised peptides from plants show molluscicidal activity against the rice pest Pomacea canaliculata (golden apple snail). J Agric Food Chem. 2008;56(13):5237–5241. doi: 10.1021/jf800302f
  79. Poth AG, Chan LY, Craik DJ. Cyclotides as grafting frameworks for protein engineering and drug design applications. Biopolymers. 2013;100(5):480–491. doi: 10.1002/bip.22284
  80. Poth AG, Colgrave ML, Philip R, et al. Discovery of cyclotides in the Fabaceae plant family provides new insights into the cyclization, evolution, and distribution of circular proteins. ACS Chem Biol. 2011;6(4):345–355. doi: 10.1021/cb100388j
  81. Poth AG, Mylne JS, Grassl J, et al. Cyclotides associate with leaf vasculature and are the products of a novel precursor in petunia (Solanaceae). J Biol Chem. 2012;287(32):27033–27046.doi: 10.1074/jbc.M112.370841
  82. Rajendran S, Slazak B, Mohotti S, et al. Tropical vibes from Sri Lanka — cyclotides from Viola betonicifolia by transcriptome and mass spectrometry analysis. Phytochemistry. 2021;187:112749. doi: 10.1016/j.phytochem.2021.112749
  83. Rehm FBH, Jackson MA, De Geyter E, et al. Papain-like cysteine proteases prepare plant cyclic peptide precursors for cyclization. PNAS USA. 2019;116(16):7831–7836.doi: 10.1073/pnas.1901807116
  84. Saether O, Craik DJ, Campbell ID, et al. Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry. 1995;34(13):4147–4158.doi: 10.1021/bi00013a002
  85. Sarmiento C, Camarero JA. Biotechnological applications of protein splicing. Curr Protein Pept Sci. 2019;20(5):408–424.doi: 10.2174/1389203720666190208110416
  86. Saska I, Gillon AD, Hatsugai N, et al. An asparaginyl endopeptidase mediates in vivo protein backbone cyclization. J Biol Chem. 2007;282(40):29721–29729. doi: 10.1074/jbc.M705185200
  87. Schoepke HA, Kra YR, Otto AH. Compounds with hemolytic activity from Viola tricolor and Viola arvensis. Sci Pharm. 1993;61(2):145–153.
  88. Schmidtko A, Lotsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet. 2010;375(9725):1569–1574. doi: 10.1016/S0140-6736(10)60354-6
  89. Slazak B, Haugmo T, Badyra B, Göransson U. The life cycle of cyclotides: biosynthesis and turnover in plant cells. Plant Cell Rep. 2020;39(10):1359–1367. doi: 10.1007/s00299-020-02569-1
  90. Svangard E, Goransson U, Hocaoglu Z, et al. Cytotoxic cyclotides from Viola. J Nat Prod. 2004;67(2):144–147. doi: 10.1021/np030101l
  91. Svangard E, Burman R, Gunasekera S, et al. Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes.J Nat Prod. 2007;70(4):643–647. doi: 10.1021/np070007v
  92. Svangard E, Goransson U, Smith D, et al. Primary and 3-D modelled structures of two cyclotides from Viola odorata. J Phytochemistry. 2003;64(1):135–142. doi: 10.1016/S0031-9422(03)00218-8
  93. Tang TMS, Luk LYP. Asparaginyl endopeptidases: enzymo¬logy, applications and limitations. Org Biomol Chem. 2021;19(23):5048–5062. doi: 10.1039/d1ob00608h
  94. Thongyoo P, Roqué-Rosell N, Leatherbarrow RJ, Tate EW. Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides. Org Biomol Chem. 2008;6(8):1462–1470.doi: 10.1039/b801667d
  95. Troeira Henriques S, Craik DJ. Cyclotide structure and function: The role of membrane binding and permeation. Biochemistry. 2017;56(5):669–682. doi: 10.1021/acs.biochem.6b01212
  96. Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med. 2011;17:1217–1220.doi: 10.1038/nm.2471
  97. de Veer SJ, Kan MW, Craik DJ. Cyclotides: from structure to function. Chem Rev. 2019;119(24):12375–12381.doi: 10.1021/acs.chemrev.9b00402
  98. Venkatesan J, Roy D. Cyclic cysteine knot and its strong implication on the structure and dynamics of cyclotides. Proteins. 2023;91(2):256–267. doi: 10.1002/prot.26426
  99. Wang CKL, Colgrave ML, Gustafson KR, et al. Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis. J Nat Prod. 2008;71(1):47–52. doi: 10.1021/np070393g
  100. Wong CTT, Rowlands DK, Wong C-H, et al. Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew Chem Int Ed Engl. 2012;5(23):5620–5624. doi: 10.1002/anie.201200984
  101. Zhang J, Liao B, Craik DJ, et al. Identification of two suites of cyclotide precursor genes from metallophyte Viola baoshanensis: cDNA sequence variation, alternative RNA splicing and potential cyclotide diversity. Gene. 2009;431(1–2):23–32.doi: 10.1016/j.gene.2008.11.005

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