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The Emergence of Cyclic Peptides: The Potential of Bioengineered Peptide Drugs

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International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

Studies into N- to C-terminal cyclic peptide backbone structures have provided for the lateral transition of important principles and strategies that clearly resonate within the world of bioactive peptides and peptide toxins. The ability to transform peptide biologics into stable and orally active constituents represents a major pharmacological achievement. This progression has been forthcoming and is potentially intensified by the diminishing expectations of current small organic molecule pipelines. While still in the early stages of development, cyclic peptide drug leads have gained the attention of the pharmaceutical industry, however their true potential is still very much unknown.

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References

  • Abuja PM, Zenz A, Trabi M, Craik DJ, Lohner K (2004) The cyclic antimicrobial peptide RTD-1 induces stabilized lipid-peptide domains more efficiently than its open-chain analogue. FEBS Lett 566(1–3):301–306. doi:10.1016/j.febslet.2004.03.112

    Article  PubMed  CAS  Google Scholar 

  • Adessi C, Soto C (2002) Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem 9(9):963–978

    Article  PubMed  CAS  Google Scholar 

  • Andersson L, Blomberg L, Flegel M, Lepsa L, Nilsson B, Verlander M (2000) Large-scale synthesis of peptides. Peptide Science 55(3):227–250. doi:10.1002/1097-0282(2000)55:3<227:AID-BIP50>3.0.CO;2-7

    Article  PubMed  CAS  Google Scholar 

  • Angell M (2004) Excess in the pharmaceutical industry. Can Med Assoc J 171(12):1451–1453. doi:10.1503/cmaj.1041594

    Article  Google Scholar 

  • Bergeron ZL, Bingham JP (2012) Scorpion toxins specific for potassium (K +) channels: a historical overview of peptide bioengineering. Toxins 4(11):1082–1119. doi:10.3390/toxins4111082

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bicker KL, Anguish L, Chumanevich AA, Cameron MD, Cui X, Witalison E, Subramanian V, Zhang X, Chumanevich AP, Hofseth LJ, Coonrod SA, Thompson PR (2012) D-amino acid based protein arginine deiminase inhibitors: synthesis, pharmacokinetics, and in cellulo efficacy. ACS Med Chem Lett 3(12):1081–1085

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bingham JP, Chun JB, Ruzicka MR, Li QX, Tan ZY, Kaulin YA, Englebretsen DR, Moczydlowski EG (2009) Synthesis of an iberiotoxin derivative by chemical ligation: a method for improved yields of cysteine-rich scorpion toxin peptides. Peptides 30(6):1049–1057. doi:10.1016/j.peptides.2009.03.008

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bingham JP, Mitsunaga E, Bergeron ZL (2010) Drugs from slugs–past, present and future perspectives of omega-conotoxin research. Chem Biol Interact 183(1):1–18

    Article  PubMed  CAS  Google Scholar 

  • Bingham JP, Andrews EA, Kiyabu SM, Cabalteja CC (2012) Drugs from slugs. Part II: conopeptide bioengineering. Chem Biol Interact 200(2–3):92–113. doi:10.1016/j.cbi.2012.09.021

    Article  PubMed  CAS  Google Scholar 

  • Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13(7):821–836

    Article  PubMed  CAS  Google Scholar 

  • Bruckdorfer T, Marder O, Albericio F (2004) From production of peptides in milligram amounts for research to multi-tons quantities for drugs of the future. Curr Pharm Biotechnol 5(1):29–43

    Article  PubMed  CAS  Google Scholar 

  • Calne RY (2010) Organ transplantation has come of age. Sci Prog 93(Pt 2):141–150

    Article  PubMed  Google Scholar 

  • Cascales L, Henriques ST, Kerr MC, Huang YH, Sweet MJ, Daly NL, Craik DJ (2011) Identification and characterization of a new family of cell-penetrating peptides: cyclic cell-penetrating peptides. J Biol Chem 286(42):36932–36943

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cemazar M, Craik DJ (2008) Microwave-assisted Boc-solid phase peptide synthesis of cyclic cysteine-rich peptides. J Pept Sci 14(6):683–689. doi:10.1002/psc.972

    Article  PubMed  CAS  Google Scholar 

  • Clark RJ, Craik DJ (2010) Native chemical ligation applied to the synthesis and bioengineering of circular peptides and proteins. Biopolymers 94(4):414–422. doi:10.1002/bip.21372

    Article  PubMed  CAS  Google Scholar 

  • Clark RJ, Craik DJ (2012) Engineering cyclic peptide toxins. Methods Enzymol 503:57–74

    Article  PubMed  CAS  Google Scholar 

  • Clark RJ, Jensen J, Nevin ST, Callaghan BP, Adams DJ, Craik DJ (2010) The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew Chem Int Ed Engl 49(37):6545–6548. doi:10.1002/anie.201000620

    Article  PubMed  CAS  Google Scholar 

  • Clark RJ, Akcan M, Kaas Q, Daly NL, Craik DJ (2012) Cyclization of conotoxins to improve their biopharmaceutical properties. Toxicon 59(4):446–455

    Article  PubMed  CAS  Google Scholar 

  • Craik DJ, Daly NL, Bond T, Waine C (1999) Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol 294(5):1327–1336. doi:10.1006/jmbi.1999.3383

    Article  PubMed  CAS  Google Scholar 

  • Daly NL, Craik DJ (2009) Design and therapeutic applications of cyclotides. Future medicinal chemistry 1(9):1613–1622. doi:10.4155/fmc.09.129

    Article  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(1–3):69–72

    Article  PubMed  CAS  Google Scholar 

  • Espiritu MJ, Collier AC, Bingham JP (2014) A 21st-century approach to age-old problems: the ascension of biologics in clinical therapeutics. Drug Discovery Today. doi:10.1016/j.drudis.2014.01.008

    PubMed  Google Scholar 

  • Estrada G, Villegas E, Corzo G (2007) Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs. Nat Prod Rep 24(1):145–161. doi:10.1039/b603083c

    Article  PubMed  CAS  Google Scholar 

  • Felizmenio-Quimio ME, Daly NL, Craik DJ (2001) Circular proteins in plants: solution structure of a novel macrocyclic trypsin inhibitor from Momordica cochinchinensis. J Biol Chem 276(25):22875–22882. doi:10.1074/jbc.M101666200

    Article  PubMed  CAS  Google Scholar 

  • Frazao B, Vasconcelos V, Antunes A (2012) Sea anemone (Cnidaria, Anthozoa, Actiniaria) toxins: an overview. Marine drugs 10(8):1812–1851. doi:10.3390/md10081812

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Frokjaer S, Otzen DE (2005) Protein drug stability: a formulation challenge. Nat Rev Drug Discov 4(4):298–306. doi:10.1038/nrd1695

    Article  PubMed  CAS  Google Scholar 

  • Gilon C, Halle D, Chorev M, Selinger Z, Byk G (1991) Backbone cyclization: a new method for conferring conformational constraint on peptides. Biopolymers 31(6):745–750. doi:10.1002/bip.360310619

    Article  PubMed  CAS  Google Scholar 

  • Goransson U, Svangard E, Claeson P, Bohlin L (2004) Novel strategies for isolation and characterization of cyclotides: the discovery of bioactive macrocyclic plant polypeptides in the Violaceae. Curr Protein Pept Sci 5(5):317–329

    Article  PubMed  Google Scholar 

  • Gran L (1973) On the effect of a polypeptide isolated from “Kalata–Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta pharmacologica et toxicologica 33(5):400–408

    PubMed  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(3):197–203

    Article  PubMed  CAS  Google Scholar 

  • Gustafson KR, McKee TC, Bokesch HR (2004) Anti-HIV cyclotides. Curr Protein Pept Sci 5(5):331–340

    Article  PubMed  CAS  Google Scholar 

  • Haines DJ, Swan CH, Green JR, Woodley JF (1990) Mucosal peptide hydrolase and brush-border marker enzyme activities in three regions of the small intestine of rats with experimental uraemia. Clin Sci 79(6):663–668

    PubMed  CAS  Google Scholar 

  • Hallen HE, Luo H, Scott-Craig JS, Walton JD (2007) Gene family encoding the major toxins of lethal Amanita mushrooms. Proc Natl Acad Sci USA 104(48):19097–19101. doi:10.1073/pnas.0707340104

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Herzig V, Wood DL, Newell F, Chaumeil PA, Kaas Q, Binford GJ, Nicholson GM, Gorse D, King GF (2011) ArachnoServer 2.0, an updated online resource for spider toxin sequences and structures. Nucleic Acids Res 39(Database issue):D653–657. doi:10.1093/nar/gkq1058

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jennings C, West J, Waine C, Craik D, Anderson M (2001) Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis. Proc Natl Acad Sci USA 98(19):10614–10619

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kaas Q, Yu R, Jin AH, Dutertre S, Craik DJ (2012) ConoServer: updated content, knowledge, and discovery tools in the conopeptide database. Nucleic Acids Res 40(Database issue):3

    Google Scholar 

  • Koehbach J, Attah AF, Berger A, Hellinger R, Kutchan TM, Carpenter EJ, Rolf M, Sonibare MA, Moody JO, Wong GK, Dessein S, Greger H, Gruber CW (2013a) Cyclotide discovery in Gentianales revisited-identification and characterization of cyclic cystine-knot peptides and their phylogenetic distribution in Rubiaceae plants. Biopolymers 100(5):438–452. doi:10.1002/bip.22328

    Article  PubMed  Google Scholar 

  • Koehbach J, O’Brien M, Muttenthaler M, Miazzo M, Akcan M, Elliott AG, Daly NL, Harvey PJ, Arrowsmith S, Gunasekera S, Smith TJ, Wray S, Goransson U, Dawson PE, Craik DJ, Freissmuth M, Gruber CW (2013b) Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design. Proc Natl Acad Sci USA 110(52):21183–21188. doi:10.1073/pnas.1311183110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kohli RM, Walsh CT, Burkart MD (2002) Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418(6898):658–661. doi:10.1038/nature00907

    Article  PubMed  CAS  Google Scholar 

  • Kopp F, Marahiel MA (2007) Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis. Nat Prod Rep 24(4):735–749. doi:10.1039/b613652b

    Article  PubMed  CAS  Google Scholar 

  • Korsinczky ML, Clark RJ, Craik DJ (2005) Disulfide bond mutagenesis and the structure and function of the head-to-tail macrocyclic trypsin inhibitor SFTI-1. Biochemistry 44(4):1145–1153. doi:10.1021/bi048297r

    Article  PubMed  CAS  Google Scholar 

  • Lax R (2010) The future of peptide development in the pharmaceutical industry. PharManufacturing 10–15

  • Lin JH (2009) Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr Drug Metab 10(7):661–691

    Article  PubMed  CAS  Google Scholar 

  • Lovelace ES, Armishaw CJ, Colgrave ML, Wahlstrom ME, Alewood PF, Daly NL, Craik DJ (2006) Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. J Med Chem 49(22):6561–6568. doi:10.1021/jm060299h

    Article  PubMed  CAS  Google Scholar 

  • Marsault E, Peterson ML (2011) Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J Med Chem 54(7):1961–2004. doi:10.1021/jm1012374

    Article  PubMed  CAS  Google Scholar 

  • McGeary RP, Fairlie DP (1998) Macrocyclic peptidomimetics: potential for drug development. Curr Opin Drug Discov Devel 1(2):208–217

    PubMed  CAS  Google Scholar 

  • Muttenthaler M, Akondi KB, Alewood PF (2011) Structure-activity studies on alpha-conotoxins. Curr Pharm Des 17(38):4226–4241

    Article  PubMed  CAS  Google Scholar 

  • Nawae W, Hannongbua S, Ruengjitchatchawalya M (2014) Defining the membrane disruption mechanism of kalata B1 via coarse-grained molecular dynamics simulations. Scientific reports 4:3933. doi:10.1038/srep03933

    Article  PubMed  PubMed Central  Google Scholar 

  • Pade V, Stavchansky S (1997) Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model. Pharmaceut Res 14(9):1210–1215. doi:10.1023/A:1012111008617

    Article  CAS  Google Scholar 

  • Parenty A, Moreau X, Campagne JM (2006) Macrolactonizations in the total synthesis of natural products. Chem Rev 106(3):911–939. doi:10.1021/cr0301402

    Article  PubMed  CAS  Google Scholar 

  • Purcell RT, Lockey RF (2008) Immunologic responses to therapeutic biologic agents. J Investig Allergol Clin Immunol 18(5):335–342

    PubMed  CAS  Google Scholar 

  • Reichert JM (2008) Monoclonal Antibodies as innovative therapeutics. Curr Pharm Biotechno 9(6):423–430. doi:10.2174/138920108786786358

    Article  CAS  Google Scholar 

  • Rohde H, Seitz O (2010) Ligation-desulfurization: a powerful combination in the synthesis of peptides and glycopeptides. Biopolymers 94(4):551–559. doi:10.1002/bip.21442

    Article  PubMed  CAS  Google Scholar 

  • Saether O, Craik DJ, Campbell ID, Sletten K, Juul J, Norman DG (1995) Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry 34(13):4147–4158

    Article  PubMed  CAS  Google Scholar 

  • Saladin PM, Zhang BD, Reichert JM (2009) Current trends in the clinical development of peptide therapeutics. IDrugs 12(12):779–784

    PubMed  CAS  Google Scholar 

  • Sawa N, Zendo T, Kiyofuji J, Fujita K, Himeno K, Nakayama J, Sonomoto K (2009) Identification and characterization of lactocyclicin Q, a novel cyclic bacteriocin produced by Lactococcus sp. strain QU 12. Appl Environ Microbiol 75(6):1552–1558. doi:10.1128/AEM.02299-08

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Schultz C (2013) Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis 5:5–10

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT (2007) Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther 115(2):246–270

    Article  PubMed  CAS  Google Scholar 

  • Svangard E, Burman R, Gunasekera S, Lovborg H, Gullbo J, Goransson U (2007) Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes. J Nat Prod 70(4):643–647. doi:10.1021/np070007v

    Article  PubMed  Google Scholar 

  • Svarstad HBH, Dhillion SS (2000) From norway to novartis: cyclosporin from Tolypocladium inflatum in an open access bioprospecting regime. Biodivers Conserv 9(11):1521–1541

    Article  Google Scholar 

  • Tam JP, Lu YA, Yang JL, Chiu KW (1999) An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides. Proc Natl Acad Sci USA 96(16):8913–8918

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tang YQ, Yuan J, Osapay G, Osapay K, Tran D, Miller CJ, Ouellette AJ, Selsted ME (1999) A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science 286(5439):498–502

    Article  PubMed  CAS  Google Scholar 

  • Tavassoli A, Benkovic SJ (2007) Split-intein mediated circular ligation used in the synthesis of cyclic peptide libraries in E. coli. Nat Protoc 2(5):1126–1133. doi:10.1038/nprot.2007.152

    Article  PubMed  CAS  Google Scholar 

  • Van Itallie CM, Anderson JM (2004) The molecular physiology of tight junction pores. Physiology 19:331–338. doi:10.1152/physiol.00027.2004

    Article  PubMed  Google Scholar 

  • Verdine GL, Hilinski GJ (2012) Stapled peptides for intracellular drug targets. Methods Enzymol 503:3–33. doi:10.1016/B978-0-12-396962-0.00001-X

    Article  PubMed  CAS  Google Scholar 

  • Vila-Farres X, Garcia de la Maria C, Lopez-Rojas R, Pachon J, Giralt E, Vila J (2012) In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii. Clin Microbiol Infect 18(4):383–387. doi:10.1111/j.1469-0691.2011.03581.x

    Article  PubMed  CAS  Google Scholar 

  • Winkler DA (2002) The role of quantitative structure–activity relationships (QSAR) in biomolecular discovery. Brief Bioinform 3(1):73–86

    Article  PubMed  CAS  Google Scholar 

  • Woodley JF (1994) Enzymatic barriers for GI peptide and protein delivery. Crit Rev Ther Drug Carrier Syst 11(2–3):61–95

    PubMed  CAS  Google Scholar 

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Acknowledgments

We are indebted to our sponsors, the University of Hawaii Sea Grant College Program and USDA TSTAR (# 2009-34135-20067) & HATCH (HAW00595-R) Programs, for supporting our work on peptide cyclization.

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  1. Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, University of Hawaii, Honolulu, HI, 96822, USA

    Parashar Thapa, Michael J. Espiritu, Chino Cabalteja & Jon-Paul Bingham

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  1. Parashar Thapa
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  2. Michael J. Espiritu
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  4. Jon-Paul Bingham
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Correspondence to Jon-Paul Bingham.

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Thapa, P., Espiritu, M.J., Cabalteja, C. et al. The Emergence of Cyclic Peptides: The Potential of Bioengineered Peptide Drugs. Int J Pept Res Ther 20, 545–551 (2014). https://doi.org/10.1007/s10989-014-9421-0

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