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Strategies to Enhance Metabolic Stabilities

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Cyclic Peptide Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2001))

Abstract

Macrocyclic peptides are a unique class of molecules that display a relatively constrained peptidic backbone as compared to their linear counterparts leading to the defined 3-D orientation of the constituent amino acids (pharmacophore). Although they are attractive candidates for lead discovery owing to the unique conformational features, their peptidic backbone is susceptible to proteolytic cleavage in various biological fluids that compromise their efficacy. In this chapter we review the various classical and contemporary chemical and biological approaches that have been utilized to combat the metabolic instability of macrocyclic peptides. We note that any chemical modification that helps in providing either local or global conformational rigidity to these macrocyclic peptides aids in improving their metabolic stability typically by slowing the cleavage kinetics by the proteases.

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References

  1. Henninot A, Collins JC, Nuss JM (2018) The current state of peptide drug discovery: back to the future? J Med Chem 61:1382–1414. https://doi.org/10.1021/acs.jmedchem.7b00318

    Article  CAS  PubMed  Google Scholar 

  2. Lau JL, Dunn MK (2018) Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem 26:2700–2707. https://doi.org/10.1016/j.bmc.2017.06.052

    Article  CAS  PubMed  Google Scholar 

  3. Davis AM, Plowright AT, Valeur E (2017) Directing evolution: the next revolution in drug discovery? Nat Rev Drug Discov 16:681–698. https://doi.org/10.1038/nrd.2017.146

    Article  CAS  PubMed  Google Scholar 

  4. Hosseinzadeh P, Bhardwaj G, Mulligan VK et al (2017) Comprehensive computational design of ordered peptide macrocycles. Science 358:1461–1466. https://doi.org/10.1126/science.aap7577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Roberts CJ (2014) Therapeutic protein aggregation: mechanisms, design, and control. Trends Biotechnol 32:372–380. https://doi.org/10.1016/j.tibtech.2014.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Craik DJ, Fairlie DP, Liras S et al (2013) The future of peptide-based drugs. Chem Biol Drug Des 81:136–147. https://doi.org/10.1111/cbdd.12055

    Article  CAS  PubMed  Google Scholar 

  7. Gao M, Cheng K, Yin H (2015) Targeting protein-protein interfaces using macrocyclic peptides. Biopolymers 104:310–316. https://doi.org/10.1002/bip.22625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Driggers EM, Hale SP, Lee J et al (2008) The exploration of macrocycles for drug discovery—an underexploited structural class. Nat Rev Drug Discov 7:608–624. https://doi.org/10.1038/nrd2590

    Article  CAS  PubMed  Google Scholar 

  9. Gilbreth RN, Koide S (2012) Structural insights for engineering binding proteins based on non-antibody scaffolds. Curr Opin Struct Biol 22:413–420. https://doi.org/10.1016/j.sbi.2012.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gould A, Ji Y, Aboye TL et al (2011) Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery. Curr Pharm Des 17:4294–4307

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Kessler H (1982) Peptide conformations.19. Conformation and biological-activity of cyclic-peptides. Angew Chem Int Ed 21:512–523. https://doi.org/10.1002/anie.198205121

    Article  Google Scholar 

  13. Hruby VJ (2002) Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov 1:847–858. https://doi.org/10.1038/nrd939

    Article  CAS  PubMed  Google Scholar 

  14. Weckbecker G, Lewis I, Albert R et al (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2:999–1017. https://doi.org/10.1038/nrd1255

    Article  CAS  PubMed  Google Scholar 

  15. Zorzi A, Deyle K, Heinis C (2017) Cyclic peptide therapeutics: past, present and future. Curr Opin Chem Biol 38:24–29. https://doi.org/10.1016/j.cbpa.2017.02.006

    Article  CAS  PubMed  Google Scholar 

  16. Wikberg JES, Mutulis F (2008) Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov 7:307–323. https://doi.org/10.1038/nrd2331

    Article  CAS  PubMed  Google Scholar 

  17. Alobeidi F, Castrucci AMD, Hadley ME et al (1989) Potent and prolonged acting cyclic lactam analogs of alpha-melanotropin—design based on molecular-dynamics. J Med Chem 32:2555–2561. https://doi.org/10.1021/jm00132a010

    Article  CAS  Google Scholar 

  18. Clayton AH, Lucas J, DeRogatis LR et al (2017) Phase I randomized placebo-controlled, double-blind study of the safety and tolerability of bremelanotide coadministered with ethanol in healthy male and female participants. Clin Ther 39:514–526. https://doi.org/10.1016/j.clintiera.2017.01.018

    Article  CAS  PubMed  Google Scholar 

  19. Howell SM, Fiacco SV, Takahashi TT et al (2014) Serum stable natural peptides designed by mRNA display. Sci Rep 4:6008–6012. https://doi.org/10.1038/srep06008

    Article  CAS  PubMed  Google Scholar 

  20. Morioka T, Loik ND, Hipolito CJ et al (2015) Selection-based discovery of macrocyclic peptides for the next generation therapeutics. Curr Opin Chem Biol 26:34–41. https://doi.org/10.1016/j.cbpa.2015.01.023

    Article  CAS  PubMed  Google Scholar 

  21. Sako Y, Goto Y, Murakami H et al (2008) Ribosomal synthesis of peptidase-resistant peptides closed by a nonreducible inter-side-chain bond. ACS Chem Biol 3:241–249. https://doi.org/10.1021/cb800010p

    Article  CAS  PubMed  Google Scholar 

  22. Assem N, Ferreira DJ, Wolan DW et al (2015) Acetone-linked peptides: a convergent approach for peptide macrocyclization and labeling. Angew Chem Int Ed 54:8665–8668. https://doi.org/10.1002/anie.201502607

    Article  CAS  Google Scholar 

  23. de Araujo AD, Mobli M, Castro J et al (2014) Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. Nat Commun 5:3165–3176. https://doi.org/10.1038/ncomms4165

    Article  CAS  PubMed  Google Scholar 

  24. Nutt RF, Veber DF, Saperstein R (1980) Synthesis of non-reducible bicyclic analogs of somatostatin. J Am Chem Soc 102:6539–6545. https://doi.org/10.1021/ja00541a025

    Article  CAS  Google Scholar 

  25. Kourra CMBK, Cramer N (2016) Converting disulfide bridges in native peptides to stable methylene thioacetals. Chem Sci 7:7007–7012. https://doi.org/10.1039/c6sc02285e

    Article  CAS  PubMed  Google Scholar 

  26. Chatterjee J, Gilon C, Hoffman A et al (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41:1331–1342. https://doi.org/10.1021/ar8000603

    Article  CAS  PubMed  Google Scholar 

  27. Zhang JQ, Mulumba M, Ong H et al (2017) Diversity-oriented synthesis of cyclic azapeptides by A(3)-macrocyclization provides high-affinity CD36-modulating peptidomimetics. Angew Chem Int Ed 56:6284–6288. https://doi.org/10.1002/anie.201611685

    Article  CAS  Google Scholar 

  28. Shin SBY, Yoo B, Todaro LJ et al (2007) Cyclic peptoids. J Am Chem Soc 129:3218–3225. https://doi.org/10.1021/ja066960o

    Article  CAS  PubMed  Google Scholar 

  29. Sherman DB, Spatola AF (1990) Compatibility of thioamides with reverse turn features—synthesis and conformational-analysis of 2 model cyclic pseudopeptides containing thioamides as backbone modifications. J Am Chem Soc 112:433–441. https://doi.org/10.1021/ja00157a064

    Article  CAS  Google Scholar 

  30. Choudhary A, Raines RT (2011) An evaluation of peptide-bond isosteres. Chembiochem 12:1801–1807. https://doi.org/10.1002/cbic.201100272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chatterjee J, Rechenmacher F, Kessler H (2013) N-methylation of peptides and proteins: an important element for modulating biological functions. Angew Chem Int Ed 52:254–269. https://doi.org/10.1002/anie.201205674

    Article  CAS  Google Scholar 

  32. Cody WL, He JX, Reily MD et al (1997) Design of a potent combined pseudopeptide endothelin-A/endothelin-B receptor antagonist, Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21) (PD 156252): examination of its pharmacokinetic and spectral properties. J Med Chem 40:2228–2240. https://doi.org/10.1021/jm970161m

    Article  CAS  PubMed  Google Scholar 

  33. Biron E, Chatterjee J, Ovadia O et al (2008) Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew Chem Int Ed 47:2595–2599. https://doi.org/10.1002/anie.200705797

    Article  CAS  Google Scholar 

  34. Cort JH, Schuck O, Stribrna J et al (1975) Role of disulfide bridge and C-terminal tripeptide in antidiuretic action of vasopressin in man and rat. Kidney Int 8:292–302. https://doi.org/10.1038/ki.1975.116

    Article  CAS  PubMed  Google Scholar 

  35. Zaoral M, Kolc J, Sorm F (1966) Synthesis of D-Arg8- and D-Lys8- Vasopressin. Collect Czech Chem C 31:382–383. https://doi.org/10.1135/cccc19660382

    Article  CAS  Google Scholar 

  36. Bauer W, Briner U, Doepfner W et al (1982) Sms 201-995—a very potent and selective octapeptide analog of somatostatin with prolonged action. Life Sci 31:1133–1140. https://doi.org/10.1016/0024-3205(82)90087-X

    Article  CAS  PubMed  Google Scholar 

  37. Schumacher TNM, Mayr LM, Minor DL et al (1996) Identification of D-peptide ligands through mirror-image phage display. Science 271:1854–1857. https://doi.org/10.1126/science.271.5257.1854

    Article  CAS  PubMed  Google Scholar 

  38. Eckert DM, Malashkevich VN, Hong LH et al (1999) Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 99:103–115. https://doi.org/10.1016/S0092-8674(00)80066-5

    Article  CAS  PubMed  Google Scholar 

  39. Goodman M, Chorev M (1979) Concept of linear modified retro-peptide structures. Acc Chem Res 12:1–7. https://doi.org/10.1021/ar50133a001

    Article  CAS  Google Scholar 

  40. Wermuth J, Goodman SL, Jonczyk A et al (1997) Stereoisomerism and biological activity of the selective and superactive alpha(v)beta(3) integrin inhibitor cyclo(-RGDfV-) and its retro-inverso peptide. J Am Chem Soc 119:1328–1335. https://doi.org/10.1021/ja961908l

    Article  CAS  Google Scholar 

  41. Jameson BA, Mcdonnell JM, Marini JC et al (1994) A rationally designed Cd4 analog inhibits experimental allergic encephalomyelitis. Nature 368:744–746. https://doi.org/10.1038/368744a0

    Article  CAS  PubMed  Google Scholar 

  42. Li C, Pazgier M, Li J et al (2010) Limitations of peptide retro-inverso isomerization in molecular mimicry. J Biol Chem 285:19572–19581. https://doi.org/10.1074/jbc.M110.116814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Batjargal S, Huang Y, Wang YXJ et al (2014) Synthesis of thioester peptides for the incorporation of thioamides into proteins by native chemical ligation. J Pept Sci 20:87–91. https://doi.org/10.1002/psc.2589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mukherjee S, Verma H, Chatterjee J (2015) Efficient site-specific incorporation of thioamides into peptides on a solid support. Org Lett 17:3150–3153. https://doi.org/10.1021/acs.orglett.5b01484

    Article  CAS  PubMed  Google Scholar 

  45. Chen X, Mietlicki-Baase EG, Barrett TM et al (2017) Thioamide substitution selectively modulates proteolysis and receptor activity of therapeutic peptide hormones. J Am Chem Soc 139:16688–16695. https://doi.org/10.1021/jacs.7b08417

    Article  CAS  PubMed  Google Scholar 

  46. Verma H, Khatri B, Chakraborti S et al (2018) Increasing the bioactive space of peptide macrocycles by thioamide substitution. Chem Sci 9:2443–2451. https://doi.org/10.1039/c7sc04671e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rhodes CA, Pei DH (2017) Bicyclic peptides as next-generation therapeutics. Chem-Eur J 23:12690–12703. https://doi.org/10.1002/chem.201702117

    Article  CAS  PubMed  Google Scholar 

  48. Heinis C, Rutherford T, Freund S et al (2009) Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat Chem Biol 5:502–507. https://doi.org/10.1038/nchembio.184

    Article  CAS  PubMed  Google Scholar 

  49. Hacker DE, Hoinka J, Iqbal ES et al (2017) Highly constrained bicyclic scaffolds for the discovery of protease-stable peptides via mRNA display. ACS Chem Biol 12:795–804. https://doi.org/10.1021/acschembio.6b01006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Angelini A, Morales-Sanfrutos J, Diderich P et al (2012) Bicyclization and tethering to albumin yields long-acting peptide antagonists. J Med Chem 55:10187–10197. https://doi.org/10.1021/jm301276e

    Article  CAS  PubMed  Google Scholar 

  51. Bartoloni M, Jin X, Marcaida MJ et al (2015) Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability. Chem Sci 6:5473–5490. https://doi.org/10.1039/c5sc01699a

    Article  CAS  PubMed  Google Scholar 

  52. Kale SS, Villequey C, Kong XD et al (2018) Cyclization of peptides with two chemical bridges affords large scaffold diversities. Nat Chem 10:715–723. https://doi.org/10.1038/s41557-018-0042-7

    Article  CAS  PubMed  Google Scholar 

  53. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001–1009. https://doi.org/10.1038/nature06526

    Article  CAS  PubMed  Google Scholar 

  54. Bruzzoni-Giovanelli H, Alezra V, Wolff N et al (2018) Interfering peptides targeting protein-protein interactions: the next generation of drugs? Drug Discov Today 23:272–285. https://doi.org/10.1016/j.drudis.2017.10.016

    Article  CAS  PubMed  Google Scholar 

  55. Marqusee S, Baldwin RL (1987) Helix stabilization by glu- ... lys+ salt bridges in short peptides of denovo design. Proc Natl Acad Sci U S A 84:8898–8902. https://doi.org/10.1073/pnas.84.24.8898

    Article  CAS  PubMed  Google Scholar 

  56. Walensky LD, Bird GH (2014) Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem 57:6275–6288. https://doi.org/10.1021/jm4011675

    Article  CAS  PubMed  Google Scholar 

  57. Wang YX, Chou DHC (2015) A thiol-ene coupling approach to native peptide stapling and macrocyclization. Angew Chem Int Ed 54:10931–10934. https://doi.org/10.1002/anie.201503975

    Article  CAS  Google Scholar 

  58. Spokoyny AM, Zou YK, Ling JJ et al (2013) A perfluoroaryl-cysteine SNAr chemistry approach to unprotected peptide stapling. J Am Chem Soc 135:5946–5949. https://doi.org/10.1021/ja400119t

    Article  CAS  PubMed  Google Scholar 

  59. Scrima M, Le Chevalier-Isaad A, Rovero P et al (2010) Cu-I-catalyzed azide-alkyne intramolecular i-to-(i+4) side-chain-to-side-chain cyclization promotes the formation of helix-like secondary structures. Eur J Org Chem 3:446–457. https://doi.org/10.1002/ejoc.200901157

    Article  CAS  Google Scholar 

  60. Mendive-Tapia L, Preciado S, Garcia J et al (2015) New peptide architectures through C–H activation stapling between tryptophan-phenylalanine/tyrosine residues. Nat Commun 6:7160–7168. https://doi.org/10.1038/ncomms8160

    Article  PubMed  Google Scholar 

  61. Patgiri A, Jochim AL, Arora PS (2008) A hydrogen bond surrogate approach for stabilization of short peptide sequences in alpha-helical conformation. Acc Chem Res 41:1289–1300. https://doi.org/10.1021/ar700264k

    Article  CAS  PubMed  Google Scholar 

  62. Bird GH, Mazzola E, Opoku-Nsiah K et al (2016) Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices. Nat Chem Biol 12:845–852. https://doi.org/10.1038/nchembio.2153

    Article  CAS  PubMed  Google Scholar 

  63. Walensky LD, Kung AL, Escher I et al (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466–1470. https://doi.org/10.1126/science.1099191

    Article  CAS  PubMed  Google Scholar 

  64. Bernal F, Tyler AF, Korsmeyer SJ et al (2007) Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc 129:2456–2457. https://doi.org/10.1021/ja0693587

    Article  CAS  PubMed  Google Scholar 

  65. Checco JW, Lee EF, Evangelista M et al (2015) alpha/beta-peptide foldamers targeting intracellular protein-protein interactions with activity in living cells. J Am Chem Soc 137:11365–11375. https://doi.org/10.1021/jacs.5b05896

    Article  CAS  PubMed  Google Scholar 

  66. Lee EF, Smith BJ, Horne WS et al (2011) Structural basis of Bcl-xL recognition by a BH3-mimetic alpha/beta-peptide generated by sequence-based design. Chembiochem 12:2025–2032. https://doi.org/10.1002/cbic.201100314

    Article  CAS  PubMed  Google Scholar 

  67. Wang D, Liao W, Arora PS (2005) Enhanced metabolic stability and protein-binding properties of artificial alpha helices derived from a hydrogen-bond surrogate: application to Bcl-xL. Angew Chem Int Ed Eng 44:6525–6529. https://doi.org/10.1002/anie.200501603

    Article  CAS  Google Scholar 

  68. Bird GH, Madani N, Perry AF et al (2010) Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc Natl Acad Sci U S A 107:14093–14098. https://doi.org/10.1073/pnas.1002713107

    Article  PubMed  Google Scholar 

  69. Shepherd NE, Hoang HN, Abbenante G et al (2005) Single turn peptide alpha helices with exceptional stability in water. J Am Chem Soc 127:2974–2983. https://doi.org/10.1021/ja0456003

    Article  CAS  PubMed  Google Scholar 

  70. Murage EN, Gao G, Bisello A et al (2010) Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges. J Med Chem 53:6412–6420. https://doi.org/10.1021/jm100602m

    Article  CAS  PubMed  Google Scholar 

  71. Holland-Nell K, Meldal M (2011) Maintaining biological activity by using triazoles as disulfide bond mimetics. Angew Chem Int Ed Eng 50:5204–5206. https://doi.org/10.1002/anie.201005846

    Article  CAS  Google Scholar 

  72. Park JH, Waters ML (2013) Positional effects of click cyclization on beta-hairpin structure, stability, and function. Org Biomol Chem 11:69–77. https://doi.org/10.1039/c2ob26445e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hanold LE, Oruganty K, Ton NT et al (2015) Inhibiting EGFR dimerization using triazolyl-bridged dimerization arm mimics. PLoS One 10:e0118796. https://doi.org/10.1371/journal.pone.0118796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Srinivas N, Jetter P, Ueberbacher BJ et al (2010) Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327:1010–1013. https://doi.org/10.1126/science.1182749

    Article  CAS  PubMed  Google Scholar 

  75. Brady RM, Baell JB, Norton RS (2013) Strategies for the development of conotoxins as new therapeutic leads. Mar Drugs 11:2293–2313. https://doi.org/10.3390/md11072293

    Article  PubMed  PubMed Central  Google Scholar 

  76. Olivera BM, Cruz LJ, de Santos V et al (1987) Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry 26:2086–2090. https://doi.org/10.1021/bi00382a004

    Article  CAS  Google Scholar 

  77. Clark RJ, Fischer H, Dempster L et al (2005) Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII. Proc Natl Acad Sci U S A 102:13767–13772. https://doi.org/10.1073/pnas.0504613102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Clark RJ, Jensen J, Nevin ST et al (2010) The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew Chem Int Ed Eng 49:6545–6548. https://doi.org/10.1002/anie.201000620

    Article  CAS  Google Scholar 

  79. de Veer SJ, Weidmann J, Craik DJ (2017) Cyclotides as tools in chemical biology. Acc Chem Res 50:1557–1565. https://doi.org/10.1021/acs.accounts.7b00157

    Article  CAS  PubMed  Google Scholar 

  80. Chan LY, Gunasekera S, Henriques ST et al (2011) Engineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds. Blood 118:6709–6717. https://doi.org/10.1182/blood-2011-06-359141

    Article  CAS  PubMed  Google Scholar 

  81. Ji Y, 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. https://doi.org/10.1021/ja405108p

    Article  CAS  PubMed  Google Scholar 

  82. Chan LY, Craik DJ, Daly NL (2015) Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration. Biosci Rep 35:e00270–e00281. https://doi.org/10.1042/BSR20150210

    Article  CAS  PubMed  Google Scholar 

  83. Sable R, Durek T, Taneja V et al (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366–2374. https://doi.org/10.1021/acschembio.6b00486

    Article  CAS  PubMed  Google Scholar 

  84. Qiu YB, Taichi M, Wei N et al (2017) An orally active bradykinin B-1 receptor antagonist engineered as a bifunctional chimera of sunflower trypsin inhibitor. J Med Chem 60:504–510. https://doi.org/10.1021/acs.jmedchem.6b01011

    Article  CAS  PubMed  Google Scholar 

  85. 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. https://doi.org/10.1021/jm800704e

    Article  CAS  PubMed  Google Scholar 

  86. Wang CK, Gruber CW, Cemazar M et al (2014) Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis. ACS Chem Biol 9:156–163. https://doi.org/10.1021/cb400548s

    Article  CAS  PubMed  Google Scholar 

  87. 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. https://doi.org/10.1021/jm301468k

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Conibear AC, Chaousis S, Durek T et al (2016) Approaches to the stabilization of bioactive epitopes by grafting and peptide cyclization. Biopolymers 106:89–100. https://doi.org/10.1002/bip.22767

    Article  CAS  PubMed  Google Scholar 

  89. 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. https://doi.org/10.1021/acs.biochem.5b00529

    Article  CAS  PubMed  Google Scholar 

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  1. Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India

    Bhavesh Khatri, Venkateswara Rao Nuthakki & Jayanta Chatterjee

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  1. Bhavesh Khatri
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  2. Venkateswara Rao Nuthakki
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  3. Jayanta Chatterjee
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Correspondence to Jayanta Chatterjee .

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  1. Hit Discovery and Optimization, Pfizer R&D, Groton, CT, USA

    Gilles Goetz

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Khatri, B., Nuthakki, V.R., Chatterjee, J. (2019). Strategies to Enhance Metabolic Stabilities. In: Goetz, G. (eds) Cyclic Peptide Design. Methods in Molecular Biology, vol 2001. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9504-2_2

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