Skip to main content

Advertisement

SpringerLink
Log in

Production of bioactive cyclotides: a comprehensive overview

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Cyclotides are an emerging class of disulfide-rich plant cyclic peptides, believed to be present in plants for defence purposes. Their exceptional thermal, chemical and enzymatic stabilities make them suitable as therapeutic agents, agrochemicals, molecular imaging probes and pharmaceutical scaffolds for drug delivery. Nearly 350 cyclotides have been identified and reported to date, while more than 150,000 diverse cyclotides are estimated to occur in plants. With the current chemical identification methodologies, cyclotides can be identified even from crude extracts. This review will extensively describe the latest strategies pertaining to the screening of plants for the presence of cyclotides. Although identification of cyclotides in plants will help to explore their distribution, evolution, diversity and biological activities, natural plant extraction is not a sustainable and reliable method of such plant metabolite production. This can be attributed to several reasons such as inconsistent and non- uniform supply due to geographical and climatic conditions. Moreover, extraction of metabolites from the non-native, rare and endangered plant is not sustainable. Therefore, in vitro production technologies independent of the natural source availability are being explored to facilitate commercial applications of cyclotides. Owing to the complex structure, the chemical synthesis and recombinant microorganism-based methods of production provide limited yields of cyclotides. Production of biopharmaceutical peptides in plant cell cultures is a safe and commercially applicable alternative which can overcome some of these challenges. Hence, strategies for sustainable production of cyclotides by plant in vitro systems is discussed in-depth in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

2,4-D:

2,4-Dichlorophenoxyacetic acid

AEP:

Asparaginyl endopeptidase

BK:

Bradykinin

Boc:

tert-butyloxycarbonyl

CCK:

Cyclic cystine knot

CTPP:

C-terminal propeptide

CTR:

C-terminal tail regions

CXCR4:

G-protein coupled chemokine receptor 4

DAK:

des-Arg9 -kinestatin

DALK:

des-Arg10-[Leu9]-kallidin

EAE:

Experimental autoimmune encephalomyelitis assay

ER:

Endoplasmic reticulum

Fmoc:

9-Fluorenyl methoxy-carbonyl

GFCKs:

Growth factor cystine knots

GPCRs:

G protein-coupled receptors

ICKs:

Inhibitor cystine knots

LDA:

Larval development assays

LNcap:

Human prostate cancer

LPS:

Lipopolysaccharide

MALDI-MSI:

Matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging

MC4R:

Melanocortin receptor 4

MCoTI-II:

Momordica cochinchinensis trypsin inhibitor-II

MOG:

Myelin oligodendrocyte glycoprotein

NBB:

Naphthol blue-black

NMR:

Nuclear magnetic resonance

NOE:

Nuclear overhauser effect

NTPP:

N-terminal propeptide

NTR:

N-terminal repeats

Oak1 :

Oldenlandia affinis kalata B1 gene

PAS:

Periodic acid-Schiff

PBR1:

Parigidin-br1

PC:

Phosphatidylcholine

PDI:

Protein-disulfide isomerases

PE:

Phosphatidylethanolamine

PET-CT:

Positron emission tomography-computed tomography

SPPS:

Solid-phase peptide synthesis

TBTO:

Tri-n-butyl tin oxide

TDZ:

Thidiazuron

TLC:

Thin-layer chromatography

References

  • Abdul Ghani H, Henriques ST, Huang Y-H et al (2017) Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies. Biopolymers 108:e22927

    Google Scholar 

  • Aboye TL, Ha H, Majumder S et al (2012) Design of a novel cyclotide-based CXCR4 antagonist with anti- human immunodeficiency virus (HIV)-1 activity. J Med Chem 55:10729–10734

    PubMed  PubMed Central  CAS  Google Scholar 

  • Aboye T, Kuang Y, Neamati N et al (2015) Rapid parallel synthesis of bioactive folded cyclotides by using a tea-bag approach. ChemBioChem 16:827–833

    PubMed  PubMed Central  CAS  Google Scholar 

  • Álvarez CA, Santana PA, Luna O et al (2018) Chemical synthesis and functional analysis of Varv A cyclotide. Molecules 23:952

    PubMed Central  Google Scholar 

  • Barbeta BL, Marshall AT, Gillon AD et al (2008) Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae. Proc Natl Acad Sci USA 105:1221–1225

    PubMed  CAS  Google Scholar 

  • Bokesch HR, Pannell LK, Cochran PK et al (2001) A novel anti-HIV macrocyclic peptide from Palicourea condensata. J Nat Prod 64:249–250

    PubMed  CAS  Google Scholar 

  • Borel JF, Feurer C, Magnée C et al (1977) Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology 32:1017–1025

    PubMed  PubMed Central  CAS  Google Scholar 

  • Broussalis AM, Goransson U, Coussio JD et al (2001) First cyclotide from Hybanthus (Violaceae). Phytochem Anal 58:47–51

    CAS  Google Scholar 

  • Bruňáková K, Babincová Z, Čellárová E (2004) Selection of callus cultures of Taxus baccata L. as a potential source of paclitaxel production. Eng Life Sci 4:465–469

    Google Scholar 

  • Burman R, Strömstedt AA, Malmsten M et al (2011) Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption. Biochim Biophys Acta 1808:2665–2673

    PubMed  CAS  Google Scholar 

  • Burman R, Yeshak MY, Larsson S et al (2015) Distribution of circular proteins in plants: large-scale mapping of cyclotides in the Violaceae. Front Plant Sci 6:855

    PubMed  PubMed Central  Google Scholar 

  • Camarero JA, Campbell MJ (2019) The potential of the cyclotide scaffold for drug development. Biomedicines 7:31

    PubMed Central  CAS  Google Scholar 

  • Camarero JA, Muir TW (1997) Chemoselective backbone cyclization of unprotected peptides. Chem Commun 15:1369–1370

    Google Scholar 

  • Camarero JA, Kimura RH, Woo YHH et al (2007) Biosynthesis of a fully functional cyclotide inside living bacterial cells. ChemBioChem 8:1363–1366

    PubMed  CAS  Google Scholar 

  • Cao P, Yang Y, Uche FI et al (2018) Coupling plant-derived cyclotides to metal surfaces: an antibacterial and antibiofilm study. Int J Mol Sci 19(3):793

    PubMed Central  Google Scholar 

  • Čemažar M, Craik DJ (2006) Factors influencing the stability of cyclotides: proteins with a circular backbone and cystine knot motif. Int J Pept Res Ther 12:253–260

    Google Scholar 

  • Chen B, Colgrave ML, Daly NL et al (2005) Isolation and characterization of novel cyclotides from Viola hederaceae: solution structure and anti-HIV activity of Vhl-1, a leaf-specific expressed cyclotide. J Biol Chem 280:22395–22405

    PubMed  CAS  Google Scholar 

  • Chen B, Colgrave ML, Wang C et al (2006) Cycloviolacin H4, a hydrophobic cyclotide from Viola hederaceae. J Nat Prod 69:23–28

    PubMed  CAS  Google Scholar 

  • Claeson P, Göransson U, Johansson S et al (1998) Fractionation protocol for the isolation of polypeptides from plant biomass. J Nat Prod 61:77–81

    PubMed  CAS  Google Scholar 

  • Clark RJ, Daly NL, Craik DJ (2006) Structural plasticity of the cyclic-cystine-knot framework: implications for biological activity and drug design. Biochem J 394:85–93

    PubMed  PubMed Central  CAS  Google Scholar 

  • Colgrave ML (2015) Primary structural analysis of cyclotides. In: Craik DJ (ed) Advances in botanical research, vol 76. Academic Press, Cambridge, pp 113–154

    Google Scholar 

  • Colgrave ML, Craik DJ (2004) Thermal, chemical, and enzymatic stability of the cyclotide kalata B1: the importance of the cyclic cystine knot. Biochemistry 43:5965–5975

    PubMed  CAS  Google Scholar 

  • Colgrave ML, Kotze AC, Huang YH et al (2008a) Cyclotides: natural, circular plant peptides that possess significant activity against gastrointestinal nematode parasites of sheep. Biochemistry 47:5581–5589

    PubMed  CAS  Google Scholar 

  • Colgrave ML, Kotze AC, Ireland DC et al (2008b) The anthelmintic activity of the cyclotides: natural variants with enhanced activity. ChemBioChem 9:1939–1945

    PubMed  CAS  Google Scholar 

  • Colgrave ML, Kotze AC, Kopp S et al (2009) Anthelmintic activity of cyclotides: in vitro studies with canine and human hookworms. Acta Trop 109:163–166

    PubMed  CAS  Google Scholar 

  • Colgrave ML, Huang YH, Craik DJ et al (2010a) Cyclotide interactions with the nematode external surface. Antimicrob Agents Chemother 54:2160–2166

    PubMed  PubMed Central  CAS  Google Scholar 

  • Colgrave ML, Poth AG, Kaas Q et al (2010b) A new “era” for cyclotide sequencing. Biopolymers 94:592–601

    PubMed  CAS  Google Scholar 

  • Conlan BF, Gillon AD, Barbeta BL et al (2011) Subcellular targeting and biosynthesis of cyclotides in plant cells. Am J Bot 98:2018–2026

    PubMed  CAS  Google Scholar 

  • Conlan BF, Colgrave ML, Gillon AD et al (2012) Insights into processing and cyclization events associated with biosynthesis of the cyclic peptide kalata B1. J Biol Chem 287:28037–28046

    PubMed  PubMed Central  CAS  Google Scholar 

  • Craik DJ (2012) Host-defense activities of cyclotides. Toxins 4:139–156

    PubMed  PubMed Central  CAS  Google Scholar 

  • Craik DJ, Conibear AC (2011) The chemistry of cyclotides. J Org Chem 76:4805–4817

    PubMed  CAS  Google Scholar 

  • Craik DJ, Daly NL (2007) NMR as a tool for elucidating the structures of circular and knotted proteins. Mol BioSyst 3:257–265

    PubMed  CAS  Google Scholar 

  • Craik DJ, Du J (2017) Cyclotides as drug design scaffolds. Curr Opin Chem Biol 38:8–16

    PubMed  CAS  Google Scholar 

  • Craik DJ, Malik U (2013) Cyclotide biosynthesis. Curr Opin Chem Biol 17:546–554

    PubMed  CAS  Google Scholar 

  • Craik DJ, Daly NL, Bond T et al (1999) Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol 294:1327–1336

    PubMed  CAS  Google Scholar 

  • Craik DJ, Daly NL, Waine C (2001) The cystine knot motif in toxins and implications for drug design. Toxicon 39:43–60

    PubMed  CAS  Google Scholar 

  • Craik DJ, Cemazar M, Wang CKL, Daly NL (2006) The cyclotide family of circular miniproteins: nature’s combinatorial peptide template. Biopolymers 84:250–266

    PubMed  CAS  Google Scholar 

  • Craik DJ, Cemazar M, Daly NL (2007) The chemistry and biology of cyclotides. Curr Opin Drug Discov Dev 10:176–184

    CAS  Google Scholar 

  • Craik DJ, Kaas Q, Wang CK (2017) A practical guide to structural aspects of macrocycles (NMR, X-Ray, and modeling). In: Marsault E, Peterson ML (eds) Practical medicinal chemistry with macrocycles. Wiley, New York

    Google Scholar 

  • Craik DJ, Lee MH, Rehm FB et al (2018) Ribosomally-synthesised cyclic peptides from plants as drug leads and pharmaceutical scaffolds. Bioorg Med Chem 26:2727–2737

    PubMed  CAS  Google Scholar 

  • D’Souza C, Henriques ST, Wang CK et al (2016) Using the MCoTI-II cyclotide scaffold to design a stable cyclic peptide antagonist of SET, a protein overexpressed in human cancer. Biochemistry 55:396–405

    PubMed  Google Scholar 

  • Daly NL, Koltay A, Gustafson KR et al (1999) solution structure by NMR of circulin A: a macrocyclic knotted peptide having anti-HIV activity. J Mol Biol 285:333–345

    PubMed  CAS  Google Scholar 

  • Daly NL, Clark RJ, Craik DJ (2003) Disulfide folding pathways of cystine knot proteins: tying the knot within the circular backbone of the cyclotides. J Biol Chem 278:6314–6322

    PubMed  CAS  Google Scholar 

  • Daly NL, Gustafson KR, Craik DJ (2004) The role of the cyclic peptide backbone in the anti-HIV activity of the cyclotide kalata B1. FEBS Lett 574:69–72

    PubMed  CAS  Google Scholar 

  • Daly NL, Clark RJ, Plan MR et al (2006) Kalata B8, a novel antiviral circular protein, exhibits conformational flexibility in the cystine knot motif. Biochem J 393:619–626

    PubMed  PubMed Central  CAS  Google Scholar 

  • Daly NL, Rosengren KJ, Craik DJ (2009) Discovery, structure and biological activities of cyclotides. Adv Drug Deliv Rev 61:918–930

    PubMed  CAS  Google Scholar 

  • Daly NL, Thorstholm L, Greenwood KP et al (2013) Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor. J Biol Chem 288:36141–36148

    PubMed  PubMed Central  CAS  Google Scholar 

  • Derua R, Gustafson KR, Pannell LK (1996) Analysis of the disulfide linkage pattern in circulin A and B, HIV-inhibitory macrocyclic peptides. Biochem Biophys Res Commun 228:632–638

    PubMed  CAS  Google Scholar 

  • Deus B, Zenk MH (1982) Exploitation of plant cells for the production of natural compounds. Biotechnol Bioeng 24(9):1965–1974

    PubMed  CAS  Google Scholar 

  • Ding X, Bai D, Qian J (2014) Novel cyclotides from Hedyotis biflora inhibit proliferation and migration of pancreatic cancer cell in vitro and in vivo. Med Chem Res 23:1406–1413

    CAS  Google Scholar 

  • Dörnenburg H (2008) Plant cell culture technology—harnessing a biological approach for competitive cyclotides production. Biotechnol Lett 30:1311–1321

    PubMed  Google Scholar 

  • Dörnenburg H (2010) Cyclotide synthesis and supply: from plant to bioprocess. Biopolymers 94:602–610

    PubMed  Google Scholar 

  • Dörnenburg H, Seydel P (2008) Effect of irradiation intensity on cell growth and kalata B1 accumulation in Oldenlandia affinis cultures. Plant Cell, Tissue Organ Cult 92:93–99

    Google Scholar 

  • Dörnenburg H, Frickinger P, Seydel P (2008) Plant cell-based processes for cyclotides production. J Biotechnol 135:123–126

    PubMed  Google Scholar 

  • Du J, Chan LY, Poth AG et al (2019) Discovery and characterization of cyclic and acyclic trypsin inhibitors from Momordica dioica. J Nat Prod 82:293–300

    PubMed  CAS  Google Scholar 

  • Dutton JL, Renda RF, Waine C et al (2004) Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteins. J Biol Chem 279:46858–46867

    PubMed  CAS  Google Scholar 

  • Eliasen R, Daly NL, Wulff BS et al (2012) Design, synthesis, structural and functional characterization of novel melanocortin agonists based on the cyclotide kalata B1. J Biol Chem 287:40493–40501

    PubMed  PubMed Central  CAS  Google Scholar 

  • Esmaeili MA, Abagheri-Mahabadi N, Hashempour H et al (2016) Viola plant cyclotide Vigno 5 induces mitochondria-mediated apoptosis via cytochrome C release and caspases activation in cervical cancer cells. Fitoterapia 109:162–168

    PubMed  CAS  Google Scholar 

  • Fahradpour M, Keov P, Tognola C et al (2017) Cyclotides isolated from an ipecac root extract antagonize the corticotropin releasing factor type 1 receptor. Front Pharmacol 8:616

    PubMed  PubMed Central  Google Scholar 

  • Farhadpour M, Hashempour H, Talebpour Z et al (2016) Microwave-assisted extraction of cyclotides from Violaignobilis. Anal Biochem 497:83–89

    PubMed  CAS  Google Scholar 

  • Fensterseifer ICM, Silva ON, Malik U et al (2015) Effects of cyclotides against cutaneous infections caused by Staphylococcus aureus. Peptides 63:38–42

    PubMed  CAS  Google Scholar 

  • Gago J, Landín M, Gallego PP (2010a) A neurofuzzy logic approach for modeling plant processes: a practical case of in vitro direct rooting and acclimatization of Vitis vinifera L. Plant Sci 179:241–249

    CAS  Google Scholar 

  • Gago J, Mariana L, Gallego PP (2010b) Strengths of artificial neural networks in modelling complex plant processes. Plant Signal Behav 5:743–745

    PubMed  PubMed Central  Google Scholar 

  • Garcia AE, Camarero JA (2010) Biological activities of natural and engineered cyclotides, a novel molecular scaffold for peptide-based therapeutics. Curr Mol Pharmacol 3:153–163

    PubMed  PubMed Central  CAS  Google Scholar 

  • Georgiev MI, Weber J, Maciuk A (2009) Bioprocessing of plant cell cultures for mass production of targeted compounds. Appl Microbiol Biotechnol 83:809–823

    PubMed  CAS  Google Scholar 

  • Gerlach S, Chandra P, Roy U et al (2019) The membrane-active phytopeptide cycloviolac in O2 simultaneously targets HIV-1-infected cells and infectious viral particles to potentiate the efficacy of antiretroviral drugs. Medicines 6:33

    PubMed Central  CAS  Google Scholar 

  • Gillon AD, Saska I, Jennings CV et al (2008) Biosynthesis of circular proteins in plants. Plant J 53:505–515

    PubMed  CAS  Google Scholar 

  • Göransson U, Craik DJ (2003) Disulfide mapping of the cyclotide kalata B1. Chemical proof of the cyclic cystine knot motif. J Biol Chem 278:48188–48196

    PubMed  Google Scholar 

  • Göransson U, Luijendijk T, Johansson S et al (1999) Seven novel macrocyclic polypeptides from Viola arvensis. J Nat Prod 62:283–286

    PubMed  Google Scholar 

  • Göransson U, Broussalis AM, Claeson P (2003) Expression of Viola cyclotides by liquid chromatography-mass spectrometry and tandem mass spectrometry sequencing of intercysteine loops after introduction of charges and cleavage sites by aminoethylation. Anal Biochem 318:107–117

    PubMed  Google Scholar 

  • Göransson U, Sjögren M, Svangård E et al (2004) Reversible antifouling effect of the cyclotide cycloviolacin O2 against barnacles. J Nat Prod 67:1287–1290

    PubMed  Google Scholar 

  • Gran L (1970) An oxytocic principle found in Oldenlandia affinis DC, an indigenous Congolese drug “kalata-kalata”, used to accelerate delivery. Medd Nor Farm Selsk 12:173–180

    Google Scholar 

  • Gran L (1972) 5-Hydroxytryptamine (serotonin) isolated from Oldenlandia affinis. Medd Nor Farm Selsk 34:125–135

    CAS  Google Scholar 

  • Gran L (1973a) Oxytocic principles of Oldenlandia affinis. Lloydia J Nat Prod 36(2):174–178

    CAS  Google Scholar 

  • Gran L (1973b) On the effect of a polypeptide isolated from “kalata-kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol Toxicol (Copenh) 33:400–408

    CAS  Google Scholar 

  • Gran L, Sandberg F, Sletten K (2000) Oldenlandia affinis (R & S) DC A plant containing uteroactive peptides used in African traditional medicine. J Ethnopharmacol 70:197–203

    PubMed  CAS  Google Scholar 

  • Greenwood KP, Daly NL, Brown DL et al (2007) The cyclic cystine knot miniprotein MCoTI-II is internalized into cells by macropinocytosis. Int J Biochem Cell Biol 39:2252–2264

    PubMed  CAS  Google Scholar 

  • Gruber CW, Čemažar M, Clark RJ et al (2007) A novel plant protein-disulfide isomerase involved in the oxidative folding of cystine knot defense proteins. J Biol Chem 282:20435–20446

    PubMed  CAS  Google Scholar 

  • Gruber CW, Elliott AG, Ireland DC et al (2008) Distribution and evolution of circular miniproteins in flowering plants. Plant Cell 20:2471–2483

    PubMed  PubMed Central  CAS  Google Scholar 

  • Gründemann C, Koehbach J, Huber R et al (2012) Do plant cyclotides have potential as immunosuppressant peptides? J Nat Prod 75:167–174

    PubMed  PubMed Central  Google Scholar 

  • Gründemann C, Thell K, Lengen K et al (2013) Cyclotides suppress human t-lymphocyte proliferation by an interleukin 2-dependent mechanism. PLoS ONE 8:1–12

    Google Scholar 

  • Gründemann C, Stenberg KG, Gruber CW (2019) T20K: an immunomodulatory cyclotide on its way to the clinic. Int J Pept Res Ther 25:9–13

    Google Scholar 

  • Gunasekera S, Daly NL, Anderson MA et al (2006) Chemical synthesis and biosynthesis of the cyclotide family of circular proteins. IUBMB Life 58:515–524

    PubMed  CAS  Google Scholar 

  • Gunasekera S, Foley FM, Clark RJ et al (2008) Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J Med Chem 51:7697–7704

    PubMed  CAS  Google Scholar 

  • Gustafson KR, Sowder RC, Henderson LE et al (1994) Circulins A and B: novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J Am Chem Soc 116:9337–9338

    CAS  Google Scholar 

  • Gustafson KR, Walton LK, Sowder RC et al (2000) New circulin macrocyclic polypeptides from Chassalia parvifolia. J Nat Prod 63:176–178

    PubMed  CAS  Google Scholar 

  • Hall K, Lee TH, Daly NL et al (2012) Gly6 of kalata B1 is critical for the selective binding to phosphatidylethanolamine membranes. Biochim Biophys Acta 1818:2354–2361

    PubMed  CAS  Google Scholar 

  • Hallock YF, Sowder RC, Pannell LK et al (2000) Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J Org Chem 65:124–128

    PubMed  CAS  Google Scholar 

  • He W, Yue L, Zeng G et al (2011) Isolation and characterization of cytotoxic cyclotides from Viola philippica. Peptides 32:1719–1723

    PubMed  CAS  Google Scholar 

  • Heitz A, Hernandez JF, Gagnon J et al (2001) Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins. Biochemistry 40:7973–7983

    PubMed  CAS  Google Scholar 

  • Hellinger R, Koehbach J, Puigpinós A et al (2015a) Inhibition of human prolyl oligopeptidase activity by the cyclotide psysol 2 isolated from psychotria solitudinum. J Nat Prod 78:1073–1082

    PubMed  PubMed Central  CAS  Google Scholar 

  • Hellinger R, Koehbach J, Soltis DE et al (2015b) Peptidomics of circular cysteine-rich plant peptides: analysis of the diversity of cyclotides from viola tricolor by transcriptome and proteome mining. J Proteome Res 14:4851–4862

    PubMed  PubMed Central  CAS  Google Scholar 

  • Henriques ST, Huang YHK, Rosengren J et al (2011) Decoding the membrane activity of the cyclotide kalata B1: the importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities. J Biol Chem 286:24231–24241

    PubMed  PubMed Central  CAS  Google Scholar 

  • Henriques ST, Huang YH, Castanho MARB et al (2012) Phosphatidylethanolamine binding is a conserved feature of cyclotide-membrane interactions. J Biol Chem 287:33629–33643

    PubMed  PubMed Central  CAS  Google Scholar 

  • Henriques ST, Peacock H, Benfield AH et al (2019) Is the mirror image a true reflection? Intrinsic membrane chirality modulates peptide binding. J Am Chem Soc 141:20460–20469

    PubMed  CAS  Google Scholar 

  • Hernandez JF, Gagnon J, Chiche L et al (2000) Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry 39:5722–5730

    PubMed  CAS  Google Scholar 

  • Herrmann A, Svangård E, Claeson P et al (2006) Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2. Cell Mol Life Sci 63:235–245

    PubMed  CAS  Google Scholar 

  • Herrmann A, Burman R, Mylne JS et al (2008) The alpine violet, Viola biflora, is a rich source of cyclotides with potent cytotoxicity. Phytochemistry 69:939–952

    PubMed  CAS  Google Scholar 

  • Hu E, Wang D, Chen J et al (2015) Novel cyclotides from hedyotis diffusa induce apoptosis and inhibit proliferation and migration of prostate cancer cells. Int J Clin Exp Med 8:4059–4065

    PubMed  PubMed Central  CAS  Google Scholar 

  • Huang YH, Colgrave ML, Clark RJ et al (2010) Lysine-scanning mutagenesis reveals an amendable face of the cyclotide kalata B1 for the optimization of nematocidal activity. J Biol Chem 285:10797–10805

    PubMed  PubMed Central  CAS  Google Scholar 

  • Ireland DC, Colgrave ML, Nguyencong P et al (2006) Discovery and characterization of a linear cyclotide from Viola odorata: implications for the processing of circular proteins. J Mol Biol 357:1522–1535

    PubMed  CAS  Google Scholar 

  • Ireland DC, Wang CKL, Wilson JA et al (2007) Cyclotides as natural anti-HIV agents. Pept Sci 90:51–60

    Google Scholar 

  • Ireland DC, Clark RJ, Daly NL et al (2010) Isolation, sequencing, and structure-activity relationships of cyclotides. J Nat Prod 73:1610–1622

    PubMed  CAS  Google Scholar 

  • Jagadish K, Camarero JA (2017) Recombinant expression of cyclotides using split inteins. In: Mootz H (ed) Split inteins: methods and protocols, methods in molecular biology. Humana Press Springer, New York, pp 41–55

    Google Scholar 

  • Jagadish K, Gould A, Borra R et al (2015) Recombinant expression and phenotypic screening of a bioactive cyclotide against α-synuclein-induced cytotoxicity in baker′s yeast. Angew Chem Int Ed 54:8390–8394

    CAS  Google Scholar 

  • Jennings C, West J, Waine C et al (2001) Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis. Proc Natl Acad Sci 98:10614–10619

    PubMed  CAS  Google Scholar 

  • Jennings CV, Rosengren KJ, Daly NL et al (2005) Isolation, solution structure, and insecticidal activity of kalata B2, a circular protein with a twist: do Möbius strips exist in nature? Biochemistry 44:851–860

    PubMed  CAS  Google Scholar 

  • Ji YB, Majumder S, Millard M et al (2013) In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J Am Chem Soc 135:11623–11633

    PubMed  PubMed Central  CAS  Google Scholar 

  • Kedarisetti P, Mizianty MJ, Kaas Q et al (2014) Prediction and characterization of cyclic proteins from sequences in three domains of life. Biochim Biophys Acta J 1844:181–190

    CAS  Google Scholar 

  • Koehbach J, Attah AF, Berger A et al (2013a) Cyclotide discovery in Gentianales revisited-identification and characterization of cyclic cystine-knot peptides and their phylogenetic distribution in Rubiaceae plants. Biopolymers 100:438–452

    PubMed  CAS  Google Scholar 

  • Koehbach J, O’Brien M, Muttenthaler M et al (2013b) Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design. Proc Natl Acad Sci 110:21183–21188

    PubMed  CAS  Google Scholar 

  • Lehrer RI, Cole AM, Selsted ME (2012) θ-Defensins: cyclic peptides with endless potential. J Biol Chem 287:27014–27019

    PubMed  PubMed Central  CAS  Google Scholar 

  • Lesniak WG, Aboye T, Chatterjee S et al (2017) In vivo evaluation of an engineered cyclotide as specific CXCR4 imaging reagent. Chem Eur J 23:14469–14475

    PubMed  CAS  Google Scholar 

  • Lila MA (2004) Valuable secondary products from in vitro culture. In: Gray DJ, Trigiano RN (eds) Plant development and biotechnology. CRC Press, Boca Raton

    Google Scholar 

  • Lindholm P, Göransson U, Johansson S et al (2002) Cyclotides: a novel type of cytotoxic agents. Mol Cancer Ther 1:365–369

    PubMed  CAS  Google Scholar 

  • Liu MZ, Yang Y, Zhang SX et al (2014) A cyclotide against influenza A H1N1 virus from Viola yedoensis. Yao Xue Xue Bao 49:905–912

    PubMed  CAS  Google Scholar 

  • Luckett S, Garcia RS, Barker JJ et al (1999) High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. J Mol Biol 290:525–533

    PubMed  CAS  Google Scholar 

  • Mahatmanto T, Poth AG, Mylne JS et al (2014) A comparative study of extraction methods reveals preferred solvents for cystine knot peptide isolation from Momordica cochinchinensis seeds. Fitoterapia 95:22–33

    PubMed  CAS  Google Scholar 

  • Malagon D, Botterill B, Gray DJ et al (2013) Anthelminthic activity of the cyclotides (kalata B1 and B2) against schistosome parasites. Biopolymers 100:461–470

    PubMed  CAS  Google Scholar 

  • Mulvenna JP, Sando L, Craik DJ (2005) Processing of a 22 kDa Precursor protein to produce the circular protein Tricyclon A. Structure 13:691–701

    PubMed  CAS  Google Scholar 

  • Mulvenna JP, Wang C, Craik DJ (2006) CyBase: a database of cyclic protein sequence and structure. Nucl Acids Res 34:D192–D194

    PubMed  CAS  Google Scholar 

  • Mylne JS, Wang CK, van der Weerden NL et al (2010) Cyclotides are a component of the innate defense of Oldenlandia affinis. Biopolymers 94:635–646

    PubMed  CAS  Google Scholar 

  • Narayani M, Srivastava S (2017) Elicitation: a stimulation of stress in in vitro plant cell/tissue cultures for enhancement of secondary metabolite production. Phytochem Rev 16:1227–1252

    CAS  Google Scholar 

  • Narayani M, Chadha A, Srivastava S (2017a) Cyclotides from the Indian medicinal plant Viola odorata (Banafsha): identification and characterization. J Nat Prod 80:1972–1980

    PubMed  CAS  Google Scholar 

  • Narayani M, Chadha A, Srivastava S (2017b) Callus and cell suspension culture of Viola odorata as in vitro production platforms of known and novel cyclotides. Plant Cell, Tissue Organ Cult 130:289–299

    CAS  Google Scholar 

  • Narayani M, Sai Varsha MKN, Potunuru UR et al (2018) Production of bioactive cyclotides in somatic embryos of Viola odorata. Phytochemistry 156:135–141

    PubMed  CAS  Google Scholar 

  • Naylor MR, Bockus AT, Blanco M et al (2017) Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Curr Opin Chem Biol 38:141–147

    PubMed  CAS  Google Scholar 

  • Nguyen LA, He H, Pham-Huy C (2006) Chiral drugs: an overview. Int J Biomed Sci 2:85–100

    PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen GKT, Zhang S, Nguyen NTK et al (2011a) Discovery and characterization of novel cyclotides originated from chimeric precursors consisting of albumin-1 chain a and cyclotide domains in the fabaceae family. J Biol Chem 286:24275–24287

    PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen GKT, Zhang S, Wang W et al (2011b) Discovery of a linear cyclotide from the bracelet subfamily and its disulfide mapping by top-down mass spectrometry. J Biol Chem 286:44833–44844

    PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen GKT, Lim WH, Nguyen PQT et al (2012) Novel cyclotides and uncyclotides with highly shortened precursors from Chassalia chartacea and effects of methionine oxidation on bioactivities. J Biol Chem 287:17598–17607

    PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen GKT, Lian Y, Pang EWH et al (2013) 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 288:3370–3380

    PubMed  CAS  Google Scholar 

  • Nguyen KNT, Nguyen GKT, Nguyen PQT et al (2016) Immunostimulating and Gram-negative-specific antibacterial cyclotides from the butterfly pea (Clitoria ternatea). FEBS J 283:2067–2090

    PubMed  CAS  Google Scholar 

  • Niyomploy P, Chan LY, Poth AG et al (2016) Discovery, isolation, and structural characterization of cyclotides from Viola sumatrana Miq. Biopolymers 106:796–805

    PubMed  CAS  Google Scholar 

  • Ovesen RG, Göransson U, Hansen SH et al (2011) A liquid chromatography—electrospray ionization-mass spectrometry method for quantification of cyclotides in plants avoiding sorption during sample preparation. J Chromatogr A 1218:7964–7970

    PubMed  CAS  Google Scholar 

  • Park S, Yoo KO, Marcussen T et al (2017) Cyclotide evolution: insights from the analyses of their precursor sequences, structures and distribution in Violets (Viola). Front Plant Sci 8:1–19

    Google Scholar 

  • Pinto MFS, Fensterseifer ICM, Migliolo L et al (2012) Identification and structural characterization of novel cyclotide with activity against an insect pest of sugar cane. J Biol Chem 287:134–147

    PubMed  CAS  Google Scholar 

  • Pinto MFS, Silva ON, Viana JC et al (2016) Characterization of a bioactive acyclotide from Palicourea rigida. J Nat Prod 79:2767–2773

    PubMed  CAS  Google Scholar 

  • Pinto MEF, Najas JZG, Magalhães LG et al (2018) Inhibition of breast cancer cell migration by cyclotides isolated from Pombalia calceolaria. J Nat Prod 81:1203–1208

    PubMed  PubMed Central  CAS  Google Scholar 

  • Plan MRR, Göransson U, Clark RJ et al (2007) The cyclotide fingerprint in Oldenlandia affinis: elucidation of chemically modified, linear and novel macrocyclic peptides. ChemBioChem 8:1001–1011

    PubMed  CAS  Google Scholar 

  • Plan MRR, Saska I, Cagauan AG et al (2008) Backbone cyclised peptides from plants show molluscicidal activity against the rice pest Pomacea canaliculate (golden apple snail). J Agr Food Chem 56:5237–5241

    CAS  Google Scholar 

  • Plan MR, Rosengren KJ, Sando L et al (2010) Structural and biochemical characteristics of the cyclotide kalata B5 from Oldenlandia affinis. Biopolymers 94:647–658

    PubMed  CAS  Google Scholar 

  • Poon S, Harris KS, Jackson MA et al (2018) Co-expression of a cyclizing asparaginyl endopeptidase enables efficient production of cyclic peptides in planta. J Exp Bot 69:633–641

    PubMed  CAS  Google Scholar 

  • Poth AG, Colgrave ML, Lyons RE et al (2011a) Discovery of an unusual biosynthetic origin for circular proteins in legumes. Proc Natl Acad Sci 108:10127–10132

    PubMed  CAS  Google Scholar 

  • Poth AG, Colgrave ML, Philip R et al (2011b) Discovery of cyclotides in the Fabaceae plant family provides new insights into the cyclization, evolution, and distribution of circular proteins. ACS Chem Biol 6:345–355

    PubMed  CAS  Google Scholar 

  • Poth AG, Mylne JS, Grassl J et al (2012) Cyclotides associate with leaf vasculature and are the products of a novel precursor in Petunia (Solanaceae). J Biol Chem 287:27033–27046

    PubMed  PubMed Central  CAS  Google Scholar 

  • Poth AG, Huang YH, Le TT et al (2019) Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold. Int J Pharm 565:437–446

    PubMed  CAS  Google Scholar 

  • Pränting M, Lööv C, Burman R et al (2010) The cyclotide cycloviolacin O2 from Viola odorata has potent bactericidal activity against Gram-negative bacteria. J Antimicrob Chemother 65:1964–1971

    PubMed  Google Scholar 

  • Qu H, Smithies BJ, Durek T et al (2017) Synthesis and protein engineering applications of cyclotides. Aust J Chem 70:152–161

    CAS  Google Scholar 

  • Ravipati AS, Henriques ST, Poth AG et al (2015) Lysine-rich cyclotides: a new subclass of circular knotted proteins from Violaceae. ACS Chem Biol 10:2491–2500

    PubMed  CAS  Google Scholar 

  • Ravipati AS, Poth AG, Sónia Henriques T et al (2017) Understanding the diversity and distribution of cyclotides from plants of varied genetic origin. J Nat Prod 80:1522–1530

    PubMed  CAS  Google Scholar 

  • Rehm FBH, Jackson MA, De Geyter E et al (2019) Papain-like cysteine proteases prepare plant cyclic peptide precursors for cyclization. Proc Natl Acad Sci 116:7831–7836

    PubMed  CAS  Google Scholar 

  • Roja G, Benjamin BD, Heble MR et al (1990) The Effect of plant growth regulators and nutrient conditions on growth and alkaloid production in multiple shoot cultures of Rauwolfia serpentina. Phytother Res 4(2):49–52

    CAS  Google Scholar 

  • Rosengren KJ, Daly NL, Plan MR et al (2003) Twists, knots, and rings in proteins. Structural definition of the cyclotide framework. J Biol Chem 278:8606–8616

    PubMed  CAS  Google Scholar 

  • Saether O, Craik DJ, Campbell ID et al (1995) Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry 34:4147–4158

    PubMed  CAS  Google Scholar 

  • Sando L, Henriques T, Foley F et al (2011) A synthetic mirror image of kalata b1 reveals that Cyclotide activity is independent of a protein receptor. ChemBioChem 12:2456–2462

    PubMed  PubMed Central  CAS  Google Scholar 

  • Santos RB, Abranches R, Fischer R et al (2016) Putting the spotlight back on plant suspension cultures. Front Plant Sci 7:1–12

    Google Scholar 

  • Schöpke T, Hasan Agha MI, Kraft R et al (1993) Hämolytisch aktive komponenten aus Viola tricolor L. und Viola arvensis Murray. Sci Pharm 61:145–153

    Google Scholar 

  • Sen Z, Zhan XK, Jing J et al (2013) Chemosensitizing activities of cyclotides from Clitoria ternatea in paclitaxel-resistant lung cancer cells. Oncol Lett 5:641–644

    PubMed  Google Scholar 

  • Serra A, Hemu X, Nguyen GKT et al (2016) A high-throughput peptidomic strategy to decipher the molecular diversity of cyclic cysteine-rich peptides. Sci Rep 6:1–13

    Google Scholar 

  • Seydel P, Dornenburg H (2006) Establishment of in vitroplants, cell and tissue cultures from Oldenlandia affinis for the production of cyclic peptides. Plant Cell, Tissue Organ Cult 85:247–255

    Google Scholar 

  • Seydel P, Wong J, Dörnenburg H (2004) Gewinnung von Viola tricolor-Zellkulturen zur Produktion zyklischer peptide. In: Dechema workshop, pp 35–37

  • Seydel P, Gruber CW, Craik DJ et al (2007) Formation of cyclotides and variations in cyclotide expression in Oldenlandia affinis suspension cultures. Appl Microbiol Biotechnol 77:275–284

    PubMed  CAS  Google Scholar 

  • Seydel P, Walter C, Dornenburg H (2009) Scale-up of Oldenlandia affinis suspension cultures in photobioreactors for cyclotide production. Eng Life Sci 9:219–226

    CAS  Google Scholar 

  • Silva ON, Pinto MFS, Viana JFC et al (2019) Evaluation of the in vitro antitumor activity of nanostructured Cyclotides in polymers of Eudragit® L 100-55 and RS 30 D. Lett Drug Des Discov 16(4):437–445

    CAS  Google Scholar 

  • Simonsen SM, Sando L, Ireland DC et al (2005) A continent of plant defense peptide diversity: cyclotides in Australian Hybanthus (Violaceae). Plant Cell 17:3176–3189

    PubMed  PubMed Central  CAS  Google Scholar 

  • Simonsen SM, Sando L, Rosengren KJ et al (2008) Alanine scanning mutagenesis of the prototypic cyclotide reveals a cluster of residues essential for bioactivity. J Biol Chem 283:9805–9813

    PubMed  CAS  Google Scholar 

  • Skjeldal L, Gran L, Sletten K et al (2002) Refined structure and metal binding site of the kalata B1 peptide. Arch Biochem Biophys 399:142–148

    PubMed  CAS  Google Scholar 

  • Slazak B, Jacobsson E, Kuta E et al (2015a) Exogenous plant hormones and cyclotide expression in Viola uliginosa (Violaceae). Phytochemistry 117:527–536

    PubMed  CAS  Google Scholar 

  • Slazak B, Sliwinska E, Saługa M et al (2015b) Micropropagation of Viola uliginosa (Violaceae) for endangered species conservation and for somaclonal variation-enhanced cyclotide biosynthesis. Plant Cell, Tissue Organ Cult 120:179–190

    CAS  Google Scholar 

  • Slazak B, Kapusta M, Malik S et al (2016) Immunolocalization of cyclotides in plant cells, tissues and organ supports their role in host defense. Planta 244(5):1029–1040

    PubMed  PubMed Central  CAS  Google Scholar 

  • Slazak B, Kapusta M, Strömstedt AA et al (2018) How does the sweet violet (Viola odorata L.) fight pathogens and pests—cyclotides as a comprehensive plant host defense system. Front Plant Sci 9:1296

    PubMed  PubMed Central  Google Scholar 

  • Sletten K, Gran L (1973) Some molecular properties of kalata peptide B-1. A uterotonic polypeptide isolated from Oldenlandia affinis DC. Medd Nor Farm Selsk 7:69–82

    Google Scholar 

  • Srivastava S, Srivastava AK (2007) Hairy root culture for mass-production of high-value secondary metabolites. Crit Rev Biotechnol 27:29–43

    PubMed  CAS  Google Scholar 

  • Strömstedt AA, Park S, Burman R et al (2017) Bactericidal activity of cyclotides where phosphatidylethanolamine-lipid selectivity determines antimicrobial spectra. Biochim Biophys Acta 1859:1986–2000

    Google Scholar 

  • Svangård E, Goransson U, Smith D et al (2003) Primary and 3-D modelled structures of two cyclotides from Viola odorata. Phytochemistry 64:135–142

    PubMed  Google Scholar 

  • Svangård E, Göransson U, Hocaoglu Z et al (2004) Cytotoxic cyclotides from Viola tricolor. J Nat Prod 67:144–147

    PubMed  Google Scholar 

  • Svangård E, Burman R, Gunasekera S et al (2007) Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes. J Nat Prod 70:643–647

    PubMed  Google Scholar 

  • Tam JP, Lu YA, Yang JL et al (1999) An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides. Proc Natl Acad Sci U S A 96:8913–8918

    PubMed  PubMed Central  CAS  Google Scholar 

  • Tang J, Wang CK, Pan X et al (2010a) Isolation and characterization of cytotoxic cyclotides from Viola tricolor. Peptides 31:1434–1440

    PubMed  CAS  Google Scholar 

  • Tang J, Wang CK, Pan X et al (2010b) Isolation and characterization of bioactive cyclotides from Viola labridorica. Helv Chim Acta 93:2287–2295

    CAS  Google Scholar 

  • Thell K, Hellinger R, Sahin E et al (2016) Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis. Proc Natl Acad Sci 113:3960–3965

    PubMed  CAS  Google Scholar 

  • Thongyoo P, Roque-Rosell N, Leatherbarrow RJ et al (2008) Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides. Org Biomol Chem 6:1462–1470

    PubMed  CAS  Google Scholar 

  • Thorstholm L, Craik DJ (2012) Discovery and applications of naturally occurring cyclic peptides. Drug Discov Today Technol 9:e13–e21

    CAS  Google Scholar 

  • Trabi M, Svangård E, Herrmann A et al (2004) Variations in cyclotide expression in Viola species. J Nat Prod 67:806–810

    PubMed  CAS  Google Scholar 

  • Uddin SJ, Muhammad T, Shafiullah M et al (2017) Single-step purification of cyclotides using affinity chromatography. Pept Sci 108:e23010

    Google Scholar 

  • Wang CKL, Colgrave ML, Gustafson KR et al (2008a) Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis. J Nat Prod 71:47–52

    PubMed  CAS  Google Scholar 

  • Wang CKL, Kaas Q, Chiche L et al (2008b) CyBase: a database of cyclic protein sequences and structures, with applications in protein discovery and engineering. Nucl Acids Res 36:206–210

    Google Scholar 

  • Wang CK, Shu-Hong H, Martin JL et al (2009) Combined x-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold. J Biol Chem 284:10672–10683

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wang CK, Wacklin HP, Craik J et al (2012) Cyclotides insert into lipid bilayers to form membrane pores and destabilize the membrane through hydrophobic and phosphoethanolamine-specific interactions. J Biol Chem 287:43884–43898

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wang CK, Gruber CW, Cemazar M et al (2014a) Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis. ACS Chem Biol 9:156–163

    PubMed  CAS  Google Scholar 

  • Wang CK, King GJ, Northfield SE et al (2014b) Racemic and quasi-racemic X-ray structures of cyclic disulfide-rich peptide drug scaffolds. Angew Chem Int Ed Engl 53:11236–11241

    PubMed  CAS  Google Scholar 

  • Wang D, Chen J, Zhu J et al (2016) Novel cyclotides from Hedyotis biflora has potent bactericidal activity against Gram-negative bacteria and E. coli drug resistance. Int J Clin Exp Med 9:9521–9526

    CAS  Google Scholar 

  • Witherup KM, Bogusky MJ, Anderson PS et al (1994) Cyclopsychotride A, a biologically active, 31-residue cyclic peptide isolated from Psychotria longipes. J Nat Prod 57:1619–1625

    PubMed  CAS  Google Scholar 

  • Wong CTT, Rowlands DK, Wong CH et al (2012) Orally active peptidic bradykinin B 1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew Chem Int Ed Engl 51:5620–5624

    PubMed  CAS  Google Scholar 

  • Xu WY, Tang J, Ji CJ et al (2008) Application of a TLC chemical method to detection of cyclotides in plants. Chin Sci Bull 53:1671–1674

    CAS  Google Scholar 

  • Yeshak MY, Burman R, Asres K et al (2011) Cyclotides from an extreme habitat: characterization of cyclic peptides from Viola abyssinica of the ethiopian highlands. J Nat Prod 74:727–731

    PubMed  CAS  Google Scholar 

  • Yeshak MY, Burman R, Eriksson C (2012) Optimization of cyclotide extraction parameters. Phytochem Lett 5:776–781

    CAS  Google Scholar 

  • Zhang RY, Thapa P, Espiritu MJ et al (2018) From nature to creation: going around in circles, the art of peptide cyclization. Bioorg Med Chem 26:1135–1150

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Babu R would like to acknowledge the Science & Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, and Confederation of Indian Industry (CII) for the Prime Minister’s Fellowship Scheme for Doctoral Research.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600 036, India

    M. Narayani, R. Babu, Anju Chadha & Smita Srivastava

Authors
  1. M. Narayani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Babu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anju Chadha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Smita Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Smita Srivastava.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Narayani, M., Babu, R., Chadha, A. et al. Production of bioactive cyclotides: a comprehensive overview. Phytochem Rev 19, 787–825 (2020). https://doi.org/10.1007/s11101-020-09682-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-020-09682-9

Keywords

Search

Navigation