Lasso Peptide Bioengineering and Bioprospecting

Part of the SpringerBriefs in Microbiology book series (BRIEFSMICROBIOL)


Lasso peptides are ribosomally synthesized, post-translationally modified peptides produced by bacteria. They share an interlocked topology, consisting of a macrolactam ring at the N-terminus and a C-terminal tail that is threaded through the ring and is firmly trapped inside. This compact and constrained structure gives high stability to lasso peptides, which can thus be applied as a molecular framework for developing bioactive peptides. The chemical and genetic diversity of lasso peptides is revealed by mining microbial genomes. This chapter will present concepts and advances on lasso peptide engineering as well as information gained from genome-mining studies. To conclude, perspectives in the lasso peptide research will be discussed.


Molecular scaffold Peptide grafting Bioengineering Genome mining Isopeptidase Signalling peptide 


  1. Aboye TL, Ha H, Majumder S, Christ F, Debyser Z, Shekhtman A, Neamati N, Camarero JA (2012) Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity. J Med Chem 55(23):10729–10734. doi:10.1021/jm301468kPubMedCrossRefPubMedCentralGoogle Scholar
  2. Benyamini H, Friedler A (2010) Using peptides to study protein-protein interactions. Future Med Chem 2(6):989–1003. doi:10.4155/fmc.10.196PubMedCrossRefGoogle Scholar
  3. 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. doi:CTMC-EPUB-20130411-5PubMedCrossRefGoogle Scholar
  4. Clarke DJ, Campopiano DJ (2007) Maturation of McjA precursor peptide into active microcin MccJ25. Org Biomol Chem 5(16):2564–2566PubMedCrossRefGoogle Scholar
  5. Craik DJ, Cemazar M, Daly NL (2007) The chemistry and biology of cyclotides. Curr Opin Drug Discov Devel 10(2):176–184PubMedGoogle Scholar
  6. Craik DJ, Swedberg JE, Mylne JS, Cemazar M (2012) Cyclotides as a basis for drug design. Expert Opin Drug Discov 7(3):179–194. doi:10.1517/17460441.2012.661554PubMedCrossRefGoogle Scholar
  7. Ducasse R, Li Y, Blond A, Zirah S, Lescop E, Goulard C, Guittet E, Pernodet JL, Rebuffat S (2012a) Sviceucin, a lasso peptide from Streptomyces sviceus: isolation and structure analysis. J Pep Sci 18(Supp. 1):67–68Google Scholar
  8. Ducasse R, Yan K-P, Goulard C, Blond A, Li Y, Lescop E, Guittet E, Rebuffat S, Zirah S (2012b) Sequence determinants governing the topology and biological activity of a lasso peptide, microcin J25. ChemBioChem 13(3):371–380Google Scholar
  9. Duquesne S, Destoumieux-Garzón D, Zirah S, Goulard C, Peduzzi J, Rebuffat S (2007) Two enzymes catalyze the maturation of a lasso peptide in Escherichia coli. Chem Biol 14(7):793–803PubMedCrossRefGoogle Scholar
  10. Gongora-Benitez M, Tulla-Puche J, Albericio F (2014) Multifaceted roles of disulfide bonds. Peptides as therapeutics. Chem Rev 114(2):901–926. doi:10.1021/cr400031zPubMedCrossRefGoogle Scholar
  11. Gunasekera S, Foley FM, Clark RJ, Sando L, Fabri LJ, Craik DJ, Daly NL (2008) Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides. J Med Chem 51(24):7697–7704. doi:10.1021/jm800704ePubMedCrossRefGoogle Scholar
  12. Hegemann JD, Zimmermann M, Xie X, Marahiel MA (2013a) Caulosegnins I-III: a highly diverse group of lasso peptides derived from a single biosynthetic gene cluster. J Am Chem Soc 135(1):210–222. doi:10.1021/ja308173bGoogle Scholar
  13. Hegemann JD, Zimmermann M, Zhu S, Klug D, Marahiel MA (2013b) Lasso peptides from proteobacteria: genome mining employing heterologous expression and mass spectrometry. Biopolymers. doi:10.1002/bip.22326Google Scholar
  14. Hegemann JD, Zimmermann M, Zhu S, Steuber H, Harms K, Xie X, Marahiel MA (2014) Xanthomonins I-III: a new class of lasso peptides with a seven-residue macrolactam ring. Angew Chem Int Ed Engl. doi:10.1002/anie.201309267Google Scholar
  15. Jagadish K, Camarero JA (2010) Cyclotides, a promising molecular scaffold for peptide-based therapeutics. Biopolymers 94(5):611–616. doi:10.1002/bip.21433PubMedCrossRefPubMedCentralGoogle Scholar
  16. Kersten RD, Yang YL, Xu Y, Cimermancic P, Nam SJ, Fenical W, Fischbach MA, Moore BS, Dorrestein PC (2011) A mass spectrometry-guided genome mining approach for natural product peptidogenomics. Nat Chem Biol 7(11):794–802Google Scholar
  17. Knappe TA, Linne U, Zirah S, Rebuffat S, Xie X, Marahiel MA (2008) Isolation and structural characterization of capistruin, a lasso peptide predicted from the genome sequence of Burkholderia thailandensis E264. J Am Chem Soc 130(34):11446–11454PubMedCrossRefGoogle Scholar
  18. Knappe TA, Linne U, Robbel L, Marahiel MA (2009) Insights into the biosynthesis and stability of the lasso peptide capistruin. Chem Biol 16(12):1290–1298. doi:10.1016/j.chembiol.2009.11.009PubMedCrossRefGoogle Scholar
  19. Knappe TA, Manzenrieder F, Mas-Moruno C, Linne U, Sasse F, Kessler H, Xie X, Marahiel MA (2011) Introducing lasso peptides as molecular scaffolds for drug design: engineering of an integrin antagonist. Angew Chem Int Ed Engl 50(37):8714–8717. doi:10.1002/anie.201102190PubMedCrossRefGoogle Scholar
  20. 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 (2013) Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design. Proc Natl Acad Sci U S A 110(52):21183–21188. doi:10.1073/pnas.1311183110PubMedCrossRefPubMedCentralGoogle Scholar
  21. Maksimov MO, Link AJ (2013) Discovery and characterization of an isopeptidase that linearizes lasso peptides. J Am Chem Soc 135(32):12038–12047. doi:10.1021/ja4054256PubMedCrossRefGoogle Scholar
  22. Maksimov MO, Pelczer I, Link AJ (2012) Precursor-centric genome-mining approach for lasso peptide discovery. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1208978109Google Scholar
  23. Pan SJ, Link AJ (2011) Sequence diversity in the lasso peptide framework: discovery of functional microcin J25 variants with multiple amino acid substitutions. J Am Chem Soc 133(13):5016–5023. doi:10.1021/ja1109634PubMedCrossRefGoogle Scholar
  24. Pavlova O, Mukhopadhyay J, Sineva E, Ebright RH, Severinov K (2008) Systematic structure-activity analysis of microcin J25. J Biol Chem 283(37):25589–25595PubMedCrossRefPubMedCentralGoogle Scholar
  25. Poth AG, Chan LY, Craik DJ (2013) Cyclotides as grafting frameworks for protein engineering and drug design applications. Biopolymers 100(5):480–491. doi:10.1002/bip.22284PubMedCrossRefGoogle Scholar
  26. Salomón RA, Farías RN (1992) Microcin 25, a novel antimicrobial peptide produced by Escherichia coli. J Bacteriol 174(22):7428–7435PubMedPubMedCentralGoogle Scholar
  27. Sato AK, Viswanathan M, Kent RB, Wood CR (2006) Therapeutic peptides: technological advances driving peptides into development. Curr Opin Biotechnol 17(6):638–642. doi:10.1016/j.copbio.2006.10.002PubMedCrossRefGoogle Scholar
  28. Severinov K, Semenova E, Kazakov A, Kazakov T, Gelfand MS (2007) Low-molecular-weight post-translationally modified microcins. Mol Microbiol 65(6):1380–1394PubMedCrossRefGoogle Scholar
  29. Shibata K, Suzawa T, Ohno T, Yamada K, Tanaka T, Tsukuda E, Matsuda Y, Yamasaki M (1998) Hybrid peptides constructed from RES-701-1, an endothelin B receptor antagonist, and endothelin; binding selectivity for endothelin receptors and their pharmacological activity. Bioorg Med Chem 6(12):2459–2467. doi:S0968089698800205PubMedCrossRefGoogle Scholar
  30. Shibata K, Suzawa T, Soga S, Mizukami T, Yamada K, Hanai N, Yamasaki M (2003) Improvement of biological activity and proteolytic stability of peptides by coupling with a cyclic peptide. Bioorg Med Chem Lett 13(15):2583–2586. doi:S0960894X03004761PubMedCrossRefGoogle Scholar
  31. Sommerhoff CP, Avrutina O, Schmoldt HU, Gabrijelcic-Geiger D, Diederichsen U, Kolmar H (2010) Engineered cystine knot miniproteins as potent inhibitors of human mast cell tryptase beta. J Mol Biol 395(1):167–175. doi:10.1016/j.jmb.2009.10.028PubMedCrossRefGoogle Scholar
  32. Soudy R, Wang L, Kaur K (2012) Synthetic peptides derived from the sequence of a lasso peptide microcin J25 show antibacterial activity. Bioorg Med Chem 20(5):1794–1800. doi:10.1016/j.bmc.2011.12.061PubMedCrossRefGoogle Scholar
  33. Thongyoo P, Bonomelli C, Leatherbarrow RJ, Tate EW (2009) Potent inhibitors of beta-tryptase and human leukocyte elastase based on the MCoTI-II scaffold. J Med Chem 52(20):6197–6200. doi:10.1021/jm901233uPubMedCrossRefGoogle Scholar
  34. Twomey D, Ross RP, Ryan M, Meaney B, Hill C (2002) Lantibiotics produced by lactic acid bacteria: structure, function and applications. Antonie Van Leeuwenhoek 82(1–4):165–185PubMedCrossRefGoogle Scholar
  35. Willey JM, van der Donk WA (2007) Lantibiotics: peptides of diverse structure and function. Annu Rev Microbiol 61:477–501. doi:10.1146/annurev.micro.61.080706.093501PubMedCrossRefGoogle Scholar
  36. Wong CT, Rowlands DK, Wong CH, Lo TW, Nguyen GK, Li HY, Tam JP (2012) Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. Angew Chem Int Ed Engl 51(23):5620–5624. doi:10.1002/anie.201200984PubMedCrossRefGoogle Scholar
  37. Zimmermann M, Hegemann JD, Xie X, Marahiel MA (2013) The astexin-1 lasso peptides: biosynthesis, stability, and structural studies. Chem Biol 20(4):558–569. doi:10.1016/j.chembiol.2013.03.013PubMedCrossRefGoogle Scholar

Copyright information

© Yanyan Li, Séverine Zirah and Sylvie Rebuffat 2015

Authors and Affiliations

  1. 1.Laboratory of Communication Molecules and Adaptation of MicroorganismsMuséum National d’Histoire Naturelle CNRSParisFrance

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