Solid Phase Protein Chemical Synthesis

  • Laurent Raibaut
  • Ouafâa El Mahdi
  • Oleg MelnykEmail author
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 363)


The chemical synthesis of peptides or small proteins is often an important step in many research projects and has stimulated the development of numerous chemical methodologies. The aim of this review is to give a substantial overview of the solid phase methods developed for the production or purification of polypeptides. The solid phase peptide synthesis (SPPS) technique has facilitated considerably the access to short peptides (<50 amino acids). However, its limitations for producing large homogeneous peptides have stimulated the development of solid phase covalent or non-covalent capture purification methods. The power of the native chemical ligation (NCL) reaction for protein synthesis in aqueous solution has also been adapted to the solid phase by the combination of novel linker technologies, cysteine protection strategies and thioester or N,S-acyl shift thioester surrogate chemistries. This review details pioneering studies and the most recent publications related to the solid phase chemical synthesis of large peptides and proteins.


solid phase peptide protein native chemical ligation covalent capture non-covalent capture 


  1. 1.
    Shimko JC, North JA, Bruns AN, Poirier MG, Ottesen JJ (2011) Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes. J Mol Biol 408(2):187–204Google Scholar
  2. 2.
    Manohar M, Mooney AM, North JA, Nakkula RJ, Picking JW, Edon A, Fishel R, Poirier MG, Ottesen JJ (2009) Acetylation of histone H3 at the nucleosome dyad alters DNA-histone binding. J Biol Chem 284(35):23312–23321Google Scholar
  3. 3.
    Chiang KP, Jensen MS, McGinty RK, Muir TW (2009) A semisynthetic strategy to generate phosphorylated and acetylated histone H2B. Chembiochem 10(13):2182–2187Google Scholar
  4. 4.
    Hejjaoui M, Butterfield S, Fauvet B, Vercruysse F, Cui J, Dikiy I, Prudent M, Olschewski D, Zhang Y, Eliezer D, Lashuel HA (2012) Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies: alpha-synuclein phosphorylation at tyrosine 125. J Am Chem Soc 134(11):5196–5210Google Scholar
  5. 5.
    He S, Bauman D, Davis JS, Loyola A, Nishioka K, Gronlund JL, Reinberg D, Meng F, Kelleher N, McCafferty DG (2003) Facile synthesis of site-specifically acetylated and methylated histone proteins: reagents for evaluation of the histone code hypothesis. Proc Natl Acad Sci U S A 100(21):12033–12038Google Scholar
  6. 6.
    Unverzagt C, Kajihara Y (2013) Chemical assembly of N-glycoproteins: a refined toolbox to address a ubiquitous posttranslational modification. Chem Soc Rev 42(10):4408–4420Google Scholar
  7. 7.
    Wang P, Dong S, Brailsford JA, Iyer K, Townsend SD, Zhang Q, Hendrickson RC, Shieh J, Moore MA, Danishefsky SJ (2012) At last: erythropoietin as a single glycoform. Angew Chem Int Ed 51(46):11576–11584Google Scholar
  8. 8.
    Piontek C, Varon Silva D, Heinlein C, Pohner C, Mezzato S, Ring P, Martin A, Schmid FX, Unverzagt C (2009) Semisynthesis of a homogeneous glycoprotein enzyme: ribonuclease C: part 2. Angew Chem Int Ed 48(11):1941–1945Google Scholar
  9. 9.
    Piontek C, Ring P, Harjes O, Heinlein C, Mezzato S, Lombana N, Pohner C, Puttner M, Varon Silva D, Martin A, Schmid FX, Unverzagt C (2009) Semisynthesis of a homogeneous glycoprotein enzyme: ribonuclease C: part 1. Angew Chem Int Ed 48(11):1936–1940Google Scholar
  10. 10.
    Kumar KS, Spasser L, Erlich LA, Bavikar SN, Brik A (2011) Total chemical synthesis of di-ubiquitin chains. Angew Chem Int Ed 49(48):9126–9131Google Scholar
  11. 11.
    Kumar KS, Bavikar SN, Spasser L, Moyal T, Ohayon S, Brik A (2011) Total chemical synthesis of a 304 amino acid K48-linked tetraubiquitin protein. Angew Chem Int Ed 50(27):6137–6141Google Scholar
  12. 12.
    Hejjaoui M, Haj-Yahya M, Kumar KS, Brik A, Lashuel HA (2011) Towards elucidation of the role of ubiquitination in the pathogenesis of Parkinson’s disease with semisynthetic ubiquitinated alpha-synuclein. Angew Chem Int Ed 50(2):405–409Google Scholar
  13. 13.
    Fierz B, Chatterjee C, McGinty RK, Bar-Dagan M, Raleigh DP, Muir TW (2011) Histone H2B ubiquitylation disrupts local and higher-order chromatin compaction. Nat Chem Biol 7(2):113–119Google Scholar
  14. 14.
    Yang R, Pasunooti KK, Li F, Liu X-W, Liu C-F (2010) Synthesis of K48-linked diubiquitin using dual native chemical ligation at lysine. Chem Commun 46(38):7199–7201Google Scholar
  15. 15.
    McGinty RK, Chatterjee C, Muir TW (2009) Semisynthesis of ubiquitylated proteins. Methods Enzymol 462:225–243Google Scholar
  16. 16.
    Boll E, Drobecq H, Ollivier N, Raibaut L, Desmet R, Vicogne J, Melnyk O (2014) A novel PEG-based solid support enables the synthesis of >50 amino-acid peptide thioesters and the total synthesis of a functional SUMO-1 peptide conjugate. Chem Sci 5:2017–2022Google Scholar
  17. 17.
    Boll E, Drobecq H, Ollivier N, Blanpain A, Raibaut L, Desmet R, Vicogne J, Melnyk O (2014) One-pot chemical synthesis of small ubiquitin-like modifier (SUMO) protein-peptide conjugates using bis(2-sulfanylethyl)amido peptide latent thioester surrogates. Nat Protoc 10:269–292Google Scholar
  18. 18.
    Pellois JP, Muir TW (2006) Semisynthetic proteins in mechanistic studies: using chemistry to go where nature can’t. Curr Opin Chem Biol 10(5):487–491Google Scholar
  19. 19.
    Fischer E, Fourneau E (1901) Ueber einige Derivate des Glykokolls. Ber Dtsch Chem Ges 34:2868–2879Google Scholar
  20. 20.
    Merrifield RB (1963) Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J Am Chem Soc 85(14):2149–2154Google Scholar
  21. 21.
    Dawson PE, Muir TW, Clark-Lewis I, Kent SB (1994) Synthesis of proteins by native chemical ligation. Science 266(5186):776–779Google Scholar
  22. 22.
    Kent SB (2009) Total chemical synthesis of proteins. Chem Soc Rev 38(2):338–351Google Scholar
  23. 23.
    Merrifield RB (1965) Automated synthesis of peptides. Science 150(3693):178–185Google Scholar
  24. 24.
    Merrifield RB, Stewart JM (1965) Automated peptide synthesis. Nature 207(996):522–523Google Scholar
  25. 25.
    Merrifield RB, Stewart JM, Jernberg N (1966) Instrument for automated synthesis of peptides. Anal Chem 38(13):1905–1914Google Scholar
  26. 26.
    Gutte B, Merrifield RB (1971) The synthesis of ribonuclease A. J Biol Chem 246(6):1922–1941Google Scholar
  27. 27.
    Kresge N, Simoni RD, Hill RL (2006) The solid phase synthesis of ribonuclease A by Robert Bruce Merrifield. J Biol Chem 281(26):e21Google Scholar
  28. 28.
    Atherton E, Fox H, Harkiss D, Logan CJ, Sheppard RC, Williams BJ (1978) A mild procedure for solid phase peptide synthesis: use of fluorenylmethoxycarbonylamino-acids. J Chem Soc Chem Commun 13:537–539Google Scholar
  29. 29.
    Fields GB, Noble RL (1990) Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 35(3):161–214Google Scholar
  30. 30.
    Coin I, Beyermann M, Bienert M (2007) Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences. Nat Protoc 2(12):3247–3256Google Scholar
  31. 31.
    El-Faham A, Albericio F (2011) Peptide coupling reagents, more than a letter soup. Chem Rev 111(11):6557–6602Google Scholar
  32. 32.
    Johnson T, Quibell M, Owen D, Sheppard RC (1993) A reversible protecting group for the amide bond in peptides. Use in the synthesis of ‘difficult sequences’. J Chem Soc Chem Commun 4:369–372Google Scholar
  33. 33.
    Isidro-Llobet A, Ãlvarez M, Albericio F (2009) Amino acid-protecting groups. Chem Rev 109(6):2455–2504Google Scholar
  34. 34.
    Mutter M, Nefzi A, Sato T, Sun X, Wahl F, Wohr T (1995) Pseudo-prolines (psi Pro) for accessing “inaccessible” peptides. Pept Res 8(3):145–153Google Scholar
  35. 35.
    Haack T, Mutter M (1992) Serine derived oxazolidines as secondary structure disrupting, solubilizing building blocks in peptide synthesis. Tetrahedron Lett 33(12):1589–1592Google Scholar
  36. 36.
    Wôhr T, Mutter M (1995) Pseudo-prolines in peptide synthesis: direct insertion of serine and threonine derived oxazolidines in dipeptides. Tetrahedron Lett 36(22):3847–3848Google Scholar
  37. 37.
    Sohma Y, Hayashi Y, Skwarczynski M, Hamada Y, Sasaki M, Kimura T, Kiso Y (2004) O-N intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence-containing bioactive peptides. Biopolymers 76(4):344–356Google Scholar
  38. 38.
    Sohma Y, Hayashi Y, Kimura M, Chiyomori Y, Taniguchi A, Sasaki M, Kimura T, Kiso Y (2005) The ‘O-acyl isopeptide method’ for the synthesis of difficult sequence-containing peptides: application to the synthesis of Alzheimer’s disease-related amyloid beta peptide (Abeta) 1–42. J Pept Sci 11(8):441–451Google Scholar
  39. 39.
    Sohma Y, Taniguchi A, Skwarczynski M, Yoshiya T, Fukao F, Kimura T, Hayashi Y, Kiso Y (2006) O-Acyl isopeptide method for the efficient synthesis of difficult sequence-containing peptides: use of O-acyl isodipeptide unit. Tetrahedron Lett 47(18):3013–3017Google Scholar
  40. 40.
    Sohma Y, Sasaki M, Hayashi Y, Kimura T, Kiso Y (2004) Design and synthesis of a novel water-soluble Aβ1-42 isopeptide: an efficient strategy for the preparation of Alzheimer’s disease-related peptide, Aβ1-42, via O-N intramolecular acyl migration reaction. Tetrahedron Lett 45(31):5965–5968Google Scholar
  41. 41.
    Carpino LA, Krause E, Sferdean CD, Schümann M, Fabian H, Bienert M, Beyermann M (2004) Synthesis of difficult peptide sequences: application of a depsipeptide technique to the Jung-Redemann 10- and 26-mers and the amyloid peptide Aβ(1–42). Tetrahedron Lett 45(40):7519–7523Google Scholar
  42. 42.
    Coin I, Dölling R, Krause E, Bienert M, Beyermann M, Sferdean CD, Carpino LA (2006) Depsipeptide methodology for solid-phase peptide synthesis: circumventing side reactions and development of an automated technique via depsidipeptide units. J Org Chem 71(16):6171–6177Google Scholar
  43. 43.
    Mutter M, Chandravarkar A, Boyat C, Lopez J, Dos Santos S, Mandal B, Mimna R, Murat K, Patiny L, Saucede L, Tuchscherer G (2004) Switch peptides in statu nascendi: induction of conformational transitions relevant to degenerative diseases. Angew Chem Int Ed 43(32):4172–4178Google Scholar
  44. 44.
    Dos Santos S, Chandravarkar A, Mandal B, Mimna R, Murat K, Saucede L, Tella P, Tuchscherer G, Mutter M (2005) Switch-peptides: controlling self-assembly of amyloid beta-derived peptides in vitro by consecutive triggering of acyl migrations. J Am Chem Soc 127(34):11888–11889Google Scholar
  45. 45.
    Guillier F, Orain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100(6):2091–2158Google Scholar
  46. 46.
    Boas U, Brask J, Jensen KJ (2009) Backbone amide linker in solid-phase synthesis. Chem Rev 109(5):2092–2118Google Scholar
  47. 47.
    James IW (1999) Linkers for solid phase organic synthesis. Tetrahedron 55(16):4855–4946Google Scholar
  48. 48.
    Lloyd-Williams P, Albericio F, Giralt E (1993) Convergent solid-phase peptide synthesis. Tetrahedron 49(48):11065–11133Google Scholar
  49. 49.
    Benz H (1994) The role of solid-phase fragment condensation (SPFC) in peptide synthesis. Synthesis 1994(04):337–358Google Scholar
  50. 50.
    Merrifield RB (1964) Solid phase peptide synthesis. II. The synthesis of bradykinin. J Am Chem Soc 86(2):304–305Google Scholar
  51. 51.
    Merrifield RB (1964) Solid-phase peptide synthesis. III. An improved synthesis of bradykinin. Biochemistry 3(9):1385–1390Google Scholar
  52. 52.
    Stewart JM, Woolley DW (1965) Importance of the carboxyl end of bradykinin and other peptides. Nature 207(5002):1160–1161Google Scholar
  53. 53.
    Marglin B, Merrifield RB (1966) The synthesis of bovine insulin by the solid phase method. J Am Chem Soc 88(21):5051–5052Google Scholar
  54. 54.
    Lenard J, Robinson AB (1967) Use of hydrogen fluoride in Merrifield solid-phase peptide synthesis. J Am Chem Soc 89(1):181–182Google Scholar
  55. 55.
    Gutte B, Merrifield RB (1969) Total synthesis of an enzyme with ribonuclease A activity. J Am Chem Soc 91(2):501–502Google Scholar
  56. 56.
    Wang S-S, Kulesha ID (1975) Preparation of protected peptide intermediates for a synthesis of the ovine pituitary growth hormone sequence 96–135. J Org Chem 40(9):1227–1234Google Scholar
  57. 57.
    Mitchell AR, Erickson BW, Ryabtsev MN, Hodges RS, Merrifield RB (1976) tert-Butoxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin, a more acid-resistant support for solid-phase peptide synthesis. J Am Chem Soc 98(23):7357–7362Google Scholar
  58. 58.
    Merrifield RB, Bach AE (1978) 9-(2-Sulfo)fluorenylmethyloxycarbonyl chloride, a new reagent for the purification of synthetic peptides. J Org Chem 43(25):4808–4816Google Scholar
  59. 59.
    Wong TW, Merrifield RB (1980) Solid-phase synthesis of thymosin α1 using tert-butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin. Biochemistry 19(14):3233–3238Google Scholar
  60. 60.
    König W, Geiger R (1970) Eine neue Methode zur Synthese von Peptiden: Aktivierung der Carboxylgruppe mit Dicyclohexylcarbodiimid unter Zusatz von 1-Hydroxy-benzotriazolen. Chem Ber 103(3):788–798Google Scholar
  61. 61.
    Li CH, Yamashiro D, Gospodarowicz D, Kaplan SL, Van Vliet G (1983) Total synthesis of insulin-like growth factor I (somatomedin C). Proc Natl Acad Sci U S A 80(8):2216–2220Google Scholar
  62. 62.
    Tam JP, Heath WF, Merrifield RB (1982) Improved deprotection in solid phase peptide synthesis: removal of protecting groups from synthetic peptides by an SN2 mechanism with low concentrations of HF in dimethylsulfide. Tetrahedron Lett 23(43):4435–4438Google Scholar
  63. 63.
    Tam JP, Heath WF, Merrifield RB (1982) Improved deprotection in solid phase peptide synthesis: quantitative reduction of methionine sulfoxide to methionine during HF cleavage. Tetrahedron Lett 23(29):2939–2942Google Scholar
  64. 64.
    Tam JP, Heath WF, Merrifield RB (1983) An SN2 deprotection of synthetic peptides with a low concentration of hydrofluoric acid in dimethyl sulfide: evidence and application in peptide synthesis. J Am Chem Soc 105(21):6442–6455Google Scholar
  65. 65.
    Tam JP, Marquardt H, Rosberger DF, Wong TW, Todaro GJ (1984) Synthesis of biologically active rat transforming growth factor I. Nature 309(5966):376–378Google Scholar
  66. 66.
    Heath WF, Merrifield RB (1986) A synthetic approach to structure-function relationships in the murine epidermal growth factor molecule. Proc Natl Acad Sci U S A 83(17):6367–6371Google Scholar
  67. 67.
    Darke PL, Nutt RF, Brady SF, Garsky VM, Ciccarone TM, Leu CT, Lumma PK, Freidinger RM, Veber DF, Sigal IS (1988) HIV-1 protease specificity of peptide cleavage is sufficient for processing of gag and pol polyproteins. Biochem Biophys Res Commun 156(1):297–303Google Scholar
  68. 68.
    Nutt RF, Brady SF, Darke PL, Ciccarone TM, Colton CD, Nutt EM, Rodkey JA, Bennett CD, Waxman LH, Sigal IS, Anderson PS, Veber DF (1988) Chemical synthesis and enzymatic activity of a 99-residue peptide with a sequence proposed for the human immunodeficiency virus protease. Proc Natl Acad Sci U S A 85(19):7129–7133Google Scholar
  69. 69.
    Schneider J, Kent SB (1988) Enzymatic activity of a synthetic 99 residue protein corresponding to the putative HIV-1 protease. Cell 54(3):363–368Google Scholar
  70. 70.
    Miller M, Schneider J, Sathyanarayana BK, Toth MV, Marshall GR, Clawson L, Selk L, Kent SB, Wlodawer A (1989) Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 Å resolution. Science 246(4934):1149–1152Google Scholar
  71. 71.
    Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245(4918):616–621Google Scholar
  72. 72.
    Ramage R, Green J, Ogunjobi OM (1989) Solid phase peptide synthesis of ubiquitin. Tetrahedron Lett 30(16):2149–2152Google Scholar
  73. 73.
    Ramage R, Green J, Muir TW, Ogunjobi OM, Love S, Shaw K (1994) Synthetic, structural and biological studies of the ubiquitin system: the total chemical synthesis of ubiquitin. Biochem J 299:151–158Google Scholar
  74. 74.
    Barlos K, Gatos D, Schäfer W (1991) Synthesis of prothymosin α (ProTα)—a protein consisting of 109 amino acid residues. Angew Chem Int Ed 30(5):590–593Google Scholar
  75. 75.
    Barlos K, Chatzi O, Gatos D, Stavropoulos G (1991) 2-Chlorotrityl chloride resin. Studies on anchoring of Fmoc-amino acids and peptide cleavage. Int J Pept Protein Res 37(6):513–520Google Scholar
  76. 76.
    Dourtoglou V, Ziegler J-C, Gross B (1978) L’hexafluorophosphate de O-benzotriazolyl-N, N-tetramethyluronium: un reactif de couplage peptidique nouveau et efficace. Tetrahedron Lett 19(15):1269–1272Google Scholar
  77. 77.
    Milton RC, Milton SC, Kent SB (1992) Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show reciprocal chiral substrate specificity. Science 256(5062):1445–1448Google Scholar
  78. 78.
    Zawadzke LE, Berg JM (1992) A racemic protein. J Am Chem Soc 114(10):4002–4003Google Scholar
  79. 79.
    Green LM, Berg JM (1989) A retroviral Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys peptide binds metal ions: spectroscopic studies and a proposed three-dimensional structure. Proc Natl Acad Sci U S A 86(11):4047–4051Google Scholar
  80. 80.
    Schnolzer M, Alewood P, Jones A, Alewood D, Kent SB (1992) In situ neutralization in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences. Int J Pept Protein Res 40(3–4):180–193Google Scholar
  81. 81.
    Fitzgerald MC, Chernushevich I, Standing KG, Kent SBH, Whitman CP (1995) Total chemical synthesis and catalytic properties of the enzyme enantiomers L- and D-4-oxalocrotonate tautomerase. J Am Chem Soc 117(45):11075–11080Google Scholar
  82. 82.
    Schnolzer M, Rackwitz HR, Gustchina A, Laco GS, Wlodawer A, Elder JH, Kent SB (1996) Comparative properties of feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteinases prepared by total chemical synthesis. Virology 224(1):268–275Google Scholar
  83. 83.
    Ramage R, Raphy G (1992) Design on an affinity-based Nα-amino protecting group for peptide synthesis: tetrabenzo[a, c, g, i]fluorenyl-17-methyl urethanes (Tbfmoc). Tetrahedron Lett 33(3):385–388Google Scholar
  84. 84.
    Love SG, Muir TW, Ramage R, Shaw KT, Alexeev D, Sawyer L, Kelly SM, Price NC, Arnold JE, Mee MP, Mayer RJ (1997) Synthetic, structural and biological studies of the ubiquitin system: synthesis and crystal structure of an analogue containing unnatural amino acids. Biochem J 323:727–734Google Scholar
  85. 85.
    Alexeev D, Bury SM, Turner MA, Ogunjobi OM, Muir TW, Ramage R, Sawyer L (1994) Synthetic, structural and biological studies of the ubiquitin system: chemically synthesized and native ubiquitin fold into identical three-dimensional structures. Biochem J 299(Pt 1):159–163Google Scholar
  86. 86.
    Layfield R, Franklin K, Landon M, Walker G, Wang P, Ramage R, Brown A, Love S, Urquhart K, Muir T, Baker R, Mayer RJ (1999) Chemically synthesized ubiquitin extension proteins detect distinct catalytic capacities of deubiquitinating enzymes. Anal Biochem 274(1):40–49Google Scholar
  87. 87.
    Franklin K, Layfield R, Landon M, Ramage R, Brown A, Love S, Muir T, Urquhart K, Bownes M, Mayer RJ (1997) Capillary electrophoresis assay for ubiquitin carboxyl-terminal hydrolases with chemically synthesized ubiquitin-valine as substrate. Anal Biochem 247(2):305–309Google Scholar
  88. 88.
    Ball HL, King DS, Cohen FE, Prusiner SB, Baldwin MA (2001) Engineering the prion protein using chemical synthesis. J Pept Res 58(5):357–374Google Scholar
  89. 89.
    Ball H, Mascagni P (1995) N-(2-Chlorobenzyloxycarbonyloxy)-succinimide as a terminating agent for solid-phase peptide synthesis: application to a one-step purification procedure. Lett Pept Sci 2(1):49–57Google Scholar
  90. 90.
    Ball HL, Mascagni P (1992) Purification of synthetic peptides using reversible chromatographic probes based on the Fmoc molecule. Int J Pept Protein Res 40(5):370–379Google Scholar
  91. 91.
    Bonetto V, Massignan T, Chiesa R, Morbin M, Mazzoleni G, Diomede L, Angeretti N, Colombo L, Forloni G, Tagliavini F, Salmona M (2002) Synthetic miniprion PrP106. J Biol Chem 277(35):31327–31334Google Scholar
  92. 92.
    Dong CZ, Romieu A, Mounier CM, Heymans F, Roques BP, Godfroid JJ (2002) Total direct chemical synthesis and biological activities of human group IIA secretory phospholipase A2. Biochem J 365(Pt 2):505–511Google Scholar
  93. 93.
    Alexeev D, Barlow PN, Bury SM, Charrier JD, Cooper A, Hadfield D, Jamieson C, Kelly SM, Layfield R, Mayer RJ, McSparron H, Price NC, Ramage R, Sawyer L, Starkmann BA, Uhrin D, Wilken J, Young DW (2003) Synthesis, structural and biological studies of ubiquitin mutants containing (2S, 4S)-5-fluoroleucine residues strategically placed in the hydrophobic core. Chembiochem 4(9):894–896Google Scholar
  94. 94.
    Carpino LA, El-Faham A, Minor CA, Albericio F (1994) Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis. J Chem Soc Chem Commun 2:201–203Google Scholar
  95. 95.
    Abdelmoty I, Albericio F, Carpino L, Foxman B, Kates S (1994) Structural studies of reagents for peptide bond formation: crystal and molecular structures of HBTU and HATU. Lett Pept Sci 1(2):57–67Google Scholar
  96. 96.
    Carpino LA, Imazumi H, El-Faham A, Ferrer FJ, Zhang C, Lee Y, Foxman BM, Henklein P, Hanay C, Mugge C, Wenschuh H, Klose J, Beyermann M, Bienert M (2002) The uronium/guanidinium peptide coupling reagents: finally the true uronium salts. Angew Chem Int Ed 41(3):441–445Google Scholar
  97. 97.
    Rink H (1987) Solid-phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester resin. Tetrahedron Lett 28(33):3787–3790Google Scholar
  98. 98.
    White P, Keyte JW, Bailey K, Bloomberg G (2004) Expediting the Fmoc solid phase synthesis of long peptides through the application of dimethyloxazolidine dipeptides. J Pept Sci 10(1):18–26Google Scholar
  99. 99.
    Svobodova J, Cabrele C (2006) Stepwise solid-phase synthesis and spontaneous homodimerization of the helix-loop-helix protein Id3. Chembiochem 7(8):1164–1168Google Scholar
  100. 100.
    Hood CA, Fuentes G, Patel H, Page K, Menakuru M, Park JH (2008) Fast conventional Fmoc solid-phase peptide synthesis with HCTU. J Pept Sci 14(1):97–101Google Scholar
  101. 101.
    Garcia-Martin F, Quintanar-Audelo M, Garcia-Ramos Y, Cruz LJ, Gravel C, Furic R, Cote S, Tulla-Puche J, Albericio F (2006) ChemMatrix, a poly(ethylene glycol)-based support for the solid-phase synthesis of complex peptides. J Comb Chem 8(2):213–220Google Scholar
  102. 102.
    Patel H, Chantell CA, Fuentes G, Menakuru M, Park JH (2008) Resin comparison and fast automated stepwise conventional synthesis of human SDF-1α. J Pept Sci 14(12):1240–1243Google Scholar
  103. 103.
    Castro B, Dormoy JR, Evin G, Selve C (1975) Reactifs de couplage peptidique I (1) - l’hexafluorophosphate de benzotriazolyl N-oxytrisdimethylamino phosphonium (B.O.P.). Tetrahedron Lett 16(14):1219–1222Google Scholar
  104. 104.
    Coste J, Le-Nguyen D, Castro B (1990) PyBOP: a new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett 31(2):205–208Google Scholar
  105. 105.
    El Oualid F, Merkx R, Ekkebus R, Hameed DS, Smit JJ, de Jong A, Hilkmann H, Sixma TK, Ovaa H (2010) Chemical synthesis of ubiquitin, ubiquitin-based probes, and diubiquitin. Angew Chem Int Ed 49(52):10149–10153Google Scholar
  106. 106.
    Cardona V, Eberle I, Barthélémy S, Beythien J, Doerner B, Schneeberger P, Keyte J, White PD (2008) Application of Dmb-dipeptides in the Fmoc SPPS of difficult and aspartimide-prone sequences. Int J Pept Res Ther 14(4):285–292Google Scholar
  107. 107.
    Wu JC, Carr SF, Jarnagin K, Kirsher S, Barnett J, Chow J, Chan HW, Chen MS, Medzihradszky D, Yamashiro D, Santit DV (1990) Synthetic HIV-2 protease cleaves the GAG precursor of HIV-1 with the same specificity as HIV-1 protease. Arch Biochem Biophys 277(2):306–311Google Scholar
  108. 108.
    Hendrix JC, Halverson KJ, Lansbury PT (1992) A convergent synthesis of the amyloid protein of Alzheimer’s disease. J Am Chem Soc 114(20):7930–7931Google Scholar
  109. 109.
    Raibaut L, Ollivier N, Melnyk O (2012) Sequential native peptide ligation strategies for total chemical protein synthesis. Chem Soc Rev 41(21):7001–7015Google Scholar
  110. 110.
    Bode JW, Fox RM, Baucom KD (2006) Chemoselective amide ligations by decarboxylative condensations of N-alkylhydroxylamines and α-ketoacids. Angew Chem Int Ed 45(8):1248–1252Google Scholar
  111. 111.
    Ollivier N, Dheur J, Mhidia R, Blanpain A, Melnyk O (2010) Bis(2-sulfanylethyl)amino native peptide ligation. Org Lett 12(22):5238–5241Google Scholar
  112. 112.
    Saxon E, Armstrong JI, Bertozzi CR (2000) A “traceless” Staudinger ligation for the chemoselective synthesis of amide bonds. Org Lett 2(14):2141–2143Google Scholar
  113. 113.
    Nilsson BL, Kiessling LL, Raines RT (2000) Staudinger ligation: a peptide from a thioester and azide. Org Lett 2(13):1939–1941Google Scholar
  114. 114.
    Pattabiraman VR, Bode JW (2011) Rethinking amide bond synthesis. Nature 480(7378):471–479Google Scholar
  115. 115.
    Hackenberger CP, Schwarzer D (2008) Chemoselective ligation and modification strategies for peptides and proteins. Angew Chem Int Ed 47(52):10030–10074Google Scholar
  116. 116.
    Brenner M, Zimmermann JP, Wehrmüller J, Quitt P, Photaki I (1955) Eine neue Umlagerungsreaktion und ein neues Princip zum Aufbau von Peptidketten. Experientia 11(10):397–399Google Scholar
  117. 117.
    Wieland T, Bokelmann E, Bauer L, Lang HU, Lau H (1953) Uber Peptidsynthesen. 8. Mitteilung. Liebigs Ann Chem 583:129–148Google Scholar
  118. 118.
    Muir TW, Sondhi D, Cole PA (1998) Expressed protein ligation: a general method for protein engineering. Proc Natl Acad Sci U S A 95(12):6705–6710Google Scholar
  119. 119.
    Flavell RR, Muir TW (2009) Expressed protein ligation (EPL) in the study of signal transduction, ion conduction, and chromatin biology. Acc Chem Res 42(1):107–116Google Scholar
  120. 120.
    Evans TC, Benner J, Xu M-Q (1998) Semisynthesis of cytotoxic proteins using a modified protein splicing element. Protein Sci 7(11):2256–2264Google Scholar
  121. 121.
    Wintermann F, Engelbrecht S (2013) Reconstitution of the catalytic core of F-ATPase (αβ)3γ from Escherichia coli using chemically synthesized subunit γ. Angew Chem Int Ed 52(4):1309–1313Google Scholar
  122. 122.
    Bang D, Pentelute BL, Kent SB (2006) Kinetically controlled ligation for the convergent chemical synthesis of proteins. Angew Chem Int Ed 45(24):3985–3988Google Scholar
  123. 123.
    Fang G-M, Wang J-X, Liu L (2012) Convergent chemical synthesis of proteins by ligation of peptide hydrazides. Angew Chem Int Ed 51(41):10347–10350Google Scholar
  124. 124.
    Li J, Dong S, Townsend SD, Dean T, Gardella TJ, Danishefsky SJ (2012) Chemistry as an expanding resource in protein science: fully synthetic and fully active human parathyroid hormone-related protein (1–141). Angew Chem Int Ed 51(49):12263–12267Google Scholar
  125. 125.
    Bang D, Kent SB (2004) A one-pot total synthesis of crambin. Angew Chem Int Ed 43(19):2534–2538Google Scholar
  126. 126.
    Ollivier N, Vicogne J, Vallin A, Drobecq H, Desmet R, El-Mahdi O, Leclercq B, Goormachtigh G, Fafeur V, Melnyk O (2012) A one-pot three-segment ligation strategy for protein chemical synthesis. Angew Chem Int Ed 51(1):209–213Google Scholar
  127. 127.
    Li J, Li Y, He Q, Li Y, Li H, Liu L (2014) One-pot native chemical ligation of peptide hydrazides enables total synthesis of modified histones. Org Biomol Chem 12(29):5435–5441Google Scholar
  128. 128.
    White FH Jr (1960) Regeneration of enzymatic activity by airoxidation of reduced ribonuclease with observations on thiolation during reduction with thioglycolate. J Biol Chem 235:383–389Google Scholar
  129. 129.
    Anfinsen CB, Haber E (1961) Studies on the reduction and re-formation of protein disulfide bonds. J Biol Chem 236:1361–1363Google Scholar
  130. 130.
    Anfinsen CB, Haber E, Sela M, White FH Jr (1961) The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain. Proc Natl Acad Sci U S A 47:1309–1314Google Scholar
  131. 131.
    Haber E, Anfinsen CB (1961) Regeneration of enzyme activity by air oxidation of reduced subtilisin-modified ribonuclease. J Biol Chem 236:422–424Google Scholar
  132. 132.
    White FH Jr (1961) Regeneration of native secondary and tertiary structures by air oxidation of reduced ribonuclease. J Biol Chem 236:1353–1360Google Scholar
  133. 133.
    Carpino LA, Han GY (1970) 9-Fluorenylmethoxycarbonyl function, a new base-sensitive amino-protecting group. J Am Chem Soc 92(19):5748–5749Google Scholar
  134. 134.
    Carpino LA, Han GY (1972) 9-Fluorenylmethoxycarbonyl amino-protecting group. J Org Chem 37(22):3404–3409Google Scholar
  135. 135.
    Carpino L, Han G (1973) Correction. The 9-fluorenylmethoxycarbonyl amino-protecting group. J Org Chem 38(24):4218Google Scholar
  136. 136.
    Meldal M (1992) Pega: a flow stable polyethylene glycol dimethyl acrylamide copolymer for solid phase synthesis. Tetrahedron Lett 33(21):3077–3080Google Scholar
  137. 137.
    Quarrell R, Claridge TW, Weaver G, Lowe G (1996) Structure and properties of TentaGel resin beads: implications for combinatorial library chemistry. Mol Div 1(4):223–232Google Scholar
  138. 138.
    Krieger DE, Erickson BW, Merrifield RB (1976) Affinity purification of synthetic peptides. Proc Natl Acad Sci U S A 73(9):3160–3164Google Scholar
  139. 139.
    Lindeberg G, Tengborn J, Bennich H, Ragnarsson U (1978) Purification of a synthetic peptide with the aid of covalent chromatography. J Chromatogr A 156(2):366–369Google Scholar
  140. 140.
    Villain M, Vizzavona J, Rose K (2001) Covalent capture: a new tool for the purification of synthetic and recombinant polypeptides. Chem Biol 8(7):673–679Google Scholar
  141. 141.
    Liu CF, Tam JP (1994) Peptide segment ligation strategy without use of protecting groups. Proc Natl Acad Sci U S A 91(14):6584–6588Google Scholar
  142. 142.
    Vizzavona J, Villain M, Rose K (2002) Covalent capture purification of polypeptides after SPPS via a linker removable under very mild conditions. Tetrahedron Lett 43(48):8693–8696Google Scholar
  143. 143.
    Carpino LA (1993) 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive. J Am Chem Soc 115(10):4397–4398Google Scholar
  144. 144.
    Carpino LA, El-Faham A, Albericio F (1995) Efficiency in peptide coupling: 1-hydroxy-7-azabenzotriazole vs 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine. J Org Chem 60(11):3561–3564Google Scholar
  145. 145.
    Carpino LA, Imazumi H, Foxman BM, Vela MJ, Henklein P, El-Faham A, Klose J, Bienert M (2000) Comparison of the effects of 5- and 6-HOAt on model peptide coupling reactions relative to the cases for the 4- and 7-isomers. Org Lett 2(15):2253–2256Google Scholar
  146. 146.
    Nicolet BH, Shinn LA (1939) The action of periodic acid on α-amino alcohols. J Am Chem Soc 61(6):1615–1615Google Scholar
  147. 147.
    Barlow CB, Guthrie RD, Prior AM (1966) Periodate oxidation of amino-sugars. J Chem Soc Chem Commun 9:268–269Google Scholar
  148. 148.
    Cantley M, Hough L (1963) Malonaldehyde derivatives as intermediates in the periodate oxidations of amino- and acetamido-sugars. J Chem Soc 2711–2716Google Scholar
  149. 149.
    Clamp JR, Hough L (1965) The periodate oxidation of amino acids with reference to studies on glycoproteins. Biochem J 94:17–24Google Scholar
  150. 150.
    Dixon HB, Weitkamp LR (1962) Conversion of the N-terminal serine residue of corticotrophin into glycine. Biochem J 84:462–468Google Scholar
  151. 151.
    Funakoshi S, Fukuda H, Fujii N (1991) Chemoselective one-step purification method for peptides synthesized by the solid-phase technique. Proc Natl Acad Sci U S A 88(16):6981–6985Google Scholar
  152. 152.
    Canne LE, Winston RL, Kent SBH (1997) Synthesis of a versatile purification handle for use with Boc chemistry solid phase peptide synthesis. Tetrahedron Lett 38(19):3361–3364Google Scholar
  153. 153.
    Aucagne V, Valverde IE, Marceau P, Galibert M, Dendane N, Delmas AF (2012) Towards the simplification of protein synthesis: iterative solid-supported ligations with concomitant purifications. Angew Chem Int Ed 51(45):11320–11324Google Scholar
  154. 154.
    Raibaut L, Adihou H, Desmet R, Delmas AF, Aucagne V, Melnyk O (2013) Highly efficient solid phase synthesis of large polypeptides by iterative ligations of bis(2-sulfanylethyl)amido (SEA) peptide segments. Chem Sci 4:4061–4066Google Scholar
  155. 155.
    Tornoe CW, Christensen C, Meldal M (2002) Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem 67(9):3057–3064Google Scholar
  156. 156.
    Rostovtsev VV, Green LG, Fokin VV, Sharpless KB (2002) A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem Int Ed 41(14):2596–2599Google Scholar
  157. 157.
    Hara T, Tainosho A, Nakamura K, Sato T, Kawakami T, Aimoto S (2009) Peptide purification by affinity chromatography based on alpha-ketoacyl group chemistry. J Pept Sci 15(5):369–376Google Scholar
  158. 158.
    Dixon HB (1964) Transamination of peptides. Biochem J 92(3):661–666Google Scholar
  159. 159.
    Dixon HB, Moret V (1965) Removal of the N-terminal residue of a protein after transamination. Biochem J 94:463–469Google Scholar
  160. 160.
    Van Heyningen S, Dixon HB (1967) Scission of the N-terminal residue from a protein after transamination. Biochem J 104(3):63PGoogle Scholar
  161. 161.
    Van Heyningen S, Dixon HB (1969) Catalysis of transamination by acetate. Biochem J 114(4):70P–71PGoogle Scholar
  162. 162.
    Dixon HBF, Fields R (1972) Specific modification of NH2-terminal residues by transamination. Methods Enzymol 25:409–419Google Scholar
  163. 163.
    Dixon HB, Moret V (1964) Removal of the N-terminal residue of corticotrophin. Biochem J 93(3):25C–26CGoogle Scholar
  164. 164.
    Stevens J, Dixon HB (1995) The removal of 2-oxoacyl residues from the N-terminus of peptides and cystatin in non-denaturing conditions. Biochim Biophys Acta 1252(2):195–202Google Scholar
  165. 165.
    Mix H, Wilcke FW (1960) Nonenzymatic reactions between α-amino- and α-keto acids. II. Transformations between α-amino acids and pyruvates catalyzed by copper(II) ions and pyridine. Hoppe-Seylers Z Physiol Chem 318:148–158Google Scholar
  166. 166.
    Sucholeiki I, Lansbury PT (1993) An affinity chromatographic method for the purification of water-insoluble peptides. J Org Chem 58(6):1318–1324Google Scholar
  167. 167.
    Zhang M, Pokharel D, Fang S (2014) Purification of synthetic peptides using a catching full-length sequence by polymerization approach. Org Lett 16(5):1290–1293Google Scholar
  168. 168.
    El-Mahdi O, Melnyk O (2013) Alpha-oxo aldehyde or glyoxylyl group chemistry in peptide bioconjugation. Bioconjug Chem 24(5):735–765Google Scholar
  169. 169.
    Davies M, Bradley M (1997) C-terminally modified peptides and peptide libraries—another end to peptide synthesis. Angew Chem Int Ed 36(10):1097–1099Google Scholar
  170. 170.
    Davies M, Bradley M (1999) Internal resin capture-A self purification method for the synthesis of C-terminally modified peptides. Tetrahedron 55(15):4733–4746Google Scholar
  171. 171.
    Mende F, Seitz O (2007) Solid-phase synthesis of peptide thioesters with self-purification. Angew Chem Int Ed 46(24):4577–4580Google Scholar
  172. 172.
    Mende F, Beisswenger M, Seitz O (2010) Automated Fmoc-based solid-phase synthesis of peptide thioesters with self-purification effect and application in the construction of immobilized SH3 domains. J Am Chem Soc 132(32):11110–11118Google Scholar
  173. 173.
    Brown AR, Irving SL, Ramage R, Raphy G (1995) (17-Tetrabenzo[a,c,g,i]fluorenyl)methylchloroformate (TbfmocCl) a reagent for the rapid and efficient purification of synthetic peptides and proteins. Tetrahedron 51(43):11815–11830Google Scholar
  174. 174.
    Ball HL, Bertolini G, Levi S, Mascagni P (1994) Purification of synthetic peptides with the aid of reversible chromatographic probes. J Chrom A 686(1):73–83Google Scholar
  175. 175.
    Ball HL, Bertolini G, Mascagni P (1995) Affinity purification of 101 residue rat cpn10 using a reversible biotinylated probe. J Pept Sci 1(5):288–294Google Scholar
  176. 176.
    Kellam B, Chan WC, Chhabra SR, Bycroft BW (1997) Transient affinity tags based on the Dde protection/deprotection strategy: synthesis and application of 2-biotinyl-and 2-hexanoyldimedone. Tetrahedron Lett 38(30):5391–5394Google Scholar
  177. 177.
    Frank H-G, Casaretto M, Knorr K (2006) Method for solid-phase peptide synthesis and purification. WO 2006/056443, 1 June 2006Google Scholar
  178. 178.
    Porath J, Carlsson J, Olsson I, Belfrage G (1975) Metal chelate affinity chromatography, a new approach to protein fractionation. Nature 258(5536):598–599Google Scholar
  179. 179.
    Block H, Maertens B, Spriestersbach A, Brinker N, Kubicek J, Fabis R, Labahn J, Schafer F (2009) Immobilized-metal affinity chromatography (IMAC): a review. Methods Enzymol 463:439–473Google Scholar
  180. 180.
    Funakoshi S, Fukuda H, Fujii N (1993) Affinity purification method using a reversible biotinylating reagent for peptides synthesized by the solid-phase technique. J Chromatogr 638:21–27Google Scholar
  181. 181.
    Olejnik J, Sonar S, Krzymanska-Olejnik E, Rothschild KJ (1995) Photocleavable biotin derivatives: a versatile approach for the isolation of biomolecules. Proc Natl Acad Sci U S A 92(16):7590–7594Google Scholar
  182. 182.
    Roggero MA, Servis C, Corradin G (1997) A simple and rapid procedure for the purification of synthetic polypeptides by a combination of affinity chromatography and methionine chemistry. FEBS Lett 408(3):285–288Google Scholar
  183. 183.
    Shogren-Knaak MA, Imperiali B (1998) A reversible affinity tag for the purification of N-glycolyl capped peptides. Tetrahedron Lett 39(45):8241–8244Google Scholar
  184. 184.
    Zhang L, Tam JP (1996) Thiazolidine formation as a general and site-specific conjugation method for synthetic peptides and proteins. Anal Biochem 233(1):87–93Google Scholar
  185. 185.
    Melnyk O, Fehrentz JA, Martinez J, Gras-Masse H (2000) Functionalization of peptides and proteins by aldehyde or keto groups. Biopolymers 55(2):165–186Google Scholar
  186. 186.
    Gardlik S, Rajagopalan KV (1991) The mechanisms of inactivation of sulfite oxidase by periodate and arsenite. J Biol Chem 266(25):16627–16632Google Scholar
  187. 187.
    Geoghegan KF, Dallas JL, Feeney RE (1980) Periodate inactivation of ovotransferrin and human serum transferrin. J Biol Chem 255(23):11429–11434Google Scholar
  188. 188.
    Penner MH, Yamasaki RB, Osuga DT, Babin DR, Meares CF, Feeney RE (1983) Comparative oxidations of tyrosines and methionines in transferrins: human serum transferrin, human lactotransferrin, and chicken ovotransferrin. Arch Biochem Biophys 225(2):740–747Google Scholar
  189. 189.
    Geoghegan KF, Stroh JG (1992) Site-directed conjugation of nonpeptide groups to peptides and proteins via periodate oxidation of a 2-amino alcohol. Application to modification at N-terminal serine. Bioconjug Chem 3(2):138–146Google Scholar
  190. 190.
    Tesser GI, Balvert-Geers IC (1975) The methylsulfonylethyloxycarbonyl group, a new and versatile amino protective function. Int J Pept Protein Res 7(4):295–305Google Scholar
  191. 191.
    Canne L, Kent SBH, Simon R (1998) Solid phase native chemical ligation of unprotected or N-terminal cysteine protected peptides in aqueous solution US 6326468, Dec 4, 2001Google Scholar
  192. 192.
    Rinnova M, Lebl M (1996) Molecular diversity and libraries of structures: synthesis and screening. Collect Czechoslov Chem Commun 61:171–231Google Scholar
  193. 193.
    Lam KS, Lebl M, Krchnak V (1997) The “one-bead-one-compound” combinatorial library method. Chem Rev 97(2):411–448Google Scholar
  194. 194.
    Lam KS, Liu R, Miyamoto S, Lehman AL, Tuscano JM (2003) Applications of one-bead one-compound combinatorial libraries and chemical microarrays in signal transduction research. Acc Chem Res 36(6):370–377Google Scholar
  195. 195.
    Lebl M, Krchnak V, Sepetov NF, Nikolaev V, Stierandova A, Safar P, Seligmann B, Strop P, Thorpe D, Felder S, Lake DF, Lam KS, Salmon SE (1994) One bead-one structure libraries. In: Epton R (ed) Innovation and perspectives in solid phase synthesis. Mayflower Worldwide Ltd, Birmingham, pp 233–238Google Scholar
  196. 196.
    Lebl M, Krchnak V, Sepetov NF, Seligmann B, Strop P, Felder S, Lam KS (1995) One-bead-one-structure combinatorial libraries. Biopolymers 37(3):177–198Google Scholar
  197. 197.
    Holmes CP, Rybak CM (1994) Peptide reversal on solid supports: a technique for the generation of C-terminal exposed peptide libraries. In: Hodges RS, Smith JA (eds) Peptides: chemistry, structure and biology. ESCOM, Leiden, pp 992–994Google Scholar
  198. 198.
    Kania RS, Zuckermann RN, Marlowe CK (1994) Free C-terminal resin-bound peptides: reversal of peptide orientation via a cyclization/cleavage protocol. J Am Chem Soc 116(19):8835–8836Google Scholar
  199. 199.
    Mende F, Seitz O (2011) 9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide α-thioesters. Angew Chem Int Ed 50(6):1232–1240Google Scholar
  200. 200.
    Kenner GW, McDermott JR, Sheppard RC (1971) The safety catch principle in solid phase peptide synthesis. J Chem Soc D Chem Commun 12:636–637Google Scholar
  201. 201.
    Heidler P, Link A (2005) N-Acyl-N-alkyl-sulfonamide anchors derived from Kenner’s safety-catch linker: powerful tools in bioorganic and medicinal chemistry. Bioorg Med Chem 13(3):585–599Google Scholar
  202. 202.
    Backes BJ, Ellman JA (1999) An alkanesulfonamide “safety-catch” linker for solid-phase synthesis. J Org Chem 64(7):2322–2330Google Scholar
  203. 203.
    Ingenito R, Bianchi E, Fattori D, Pessi A (1999) Solid phase synthesis of peptide C-terminal thioesters by Fmoc/t-Bu chemistry. J Am Chem Soc 121(49):11369–11374Google Scholar
  204. 204.
    Shin Y, Winans KA, Backes BJ, Kent SBH, Ellman JA, Bertozzi CR (1999) Fmoc-based synthesis of peptide-α thioesters: application to the total chemical synthesis of a glycoprotein by native chemical ligation. J Am Chem Soc 121(50):11684–11689Google Scholar
  205. 205.
    Ollivier N, Behr JB, El-Mahdi O, Blanpain A, Melnyk O (2005) Fmoc solid-phase synthesis of peptide thioesters using an intramolecular N, S-acyl shift. Org Lett 7(13):2647–2650Google Scholar
  206. 206.
    Quaderer R, Hilvert D (2001) Improved synthesis of C-terminal peptide thioesters on “safety-catch” resins using LiBr/THF. Org Lett 3(20):3181–3184Google Scholar
  207. 207.
    Bycroft BW, Chan WC, Chhabra SR, Hone ND (1993) A novel lysine-protecting procedure for continuous flow solid phase synthesis of branched peptides. J Chem Soc Chem Commun 9:778–779Google Scholar
  208. 208.
    Augustyns K, Kraas W, Jung G (1998) Investigation on the stability of the Dde protecting group used in peptide synthesis: migration to an unprotected lysine. J Pept Res 51(2):127–133Google Scholar
  209. 209.
    Rajasekharan Pillai VN (1980) Photoremovable protecting groups in organic synthesis. Synthesis 1980(01):1–26Google Scholar
  210. 210.
    Klan P, Solomek T, Bochet CG, Blanc A, Givens R, Rubina M, Popik V, Kostikov A, Wirz J (2013) Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem Rev 113(1):119–191Google Scholar
  211. 211.
    Brik A, Keinan E, Dawson PE (2000) Protein synthesis by solid-phase chemical ligation using a safety catch linker. J Org Chem 65(12):3829–3835Google Scholar
  212. 212.
    Canne LE, Botti P, Simon RJ, Chen Y, Dennis EA, Kent SBH (1999) Chemical protein synthesis by solid phase ligation of unprotected peptide segments. J Am Chem Soc 121(38):8720–8727Google Scholar
  213. 213.
    Johnson EC, Durek T, Kent SB (2006) Total chemical synthesis, folding, and assay of a small protein on a water-compatible solid support. Angew Chem Int Ed 45(20):3283–3287Google Scholar
  214. 214.
    Stempfer G, Holl-Neugebauer B, Rudolph R (1996) Improved refolding of an immobilized fusion protein. Nat Biotechnol 14(3):329–334Google Scholar
  215. 215.
    Bang D, Kent SB (2005) His6 tag-assisted chemical protein synthesis. Proc Natl Acad Sci U S A 102(14):5014–5019Google Scholar
  216. 216.
    Tan Z, Shang S, Danishefsky SJ (2010) Insights into the finer issues of native chemical ligation: an approach to cascade ligations. Angew Chem Int Ed 49(49):9500–9503Google Scholar
  217. 217.
    Ueda S, Fujita M, Tamamura H, Fujii N, Otaka A (2005) Photolabile protection for one-pot sequential native chemical ligation. Chembiochem 6(11):1983–1986Google Scholar
  218. 218.
    Zheng JS, Cui HK, Fang GM, Xi WX, Liu L (2010) Chemical protein synthesis by kinetically controlled ligation of peptide O-esters. Chembiochem 11(4):511–515Google Scholar
  219. 219.
    Sato K, Shigenaga A, Tsuji K, Tsuda S, Sumikawa Y, Sakamoto K, Otaka A (2011) N-Sulfanylethylanilide peptide as a crypto-thioester peptide. Chembiochem 12(12):1840–1844Google Scholar
  220. 220.
    Okamoto R, Morooka K, Kajihara Y (2012) A synthetic approach to a peptide α-thioester from an unprotected peptide through cleavage and activation of a specific peptide bond by N-acetylguanidine. Angew Chem Int Ed 51(1):191–196Google Scholar
  221. 221.
    Jbara M, Seenaiah M, Brik A (2014) Solid phase chemical ligation employing a rink amide linker for the synthesis of histone H2B protein. Chem Commun 50:12534–12537Google Scholar
  222. 222.
    Cotton GJ, Muir TW (2000) Generation of a dual-labeled fluorescence biosensor for Crk-II phosphorylation using solid-phase expressed protein ligation. Chem Biol 7(4):253–261Google Scholar
  223. 223.
    Nilsson BL, Hondal RJ, Soellner MB, Raines RT (2003) Protein assembly by orthogonal chemical ligation methods. J Am Chem Soc 125(18):5268–5269Google Scholar
  224. 224.
    Becker CF, Hunter CL, Seidel R, Kent SB, Goody RS, Engelhard M (2003) Total chemical synthesis of a functional interacting protein pair: the protooncogene H-Ras and the Ras-binding domain of its effector c-Raf1. Proc Natl Acad Sci U S A 100(9):5075–5080Google Scholar
  225. 225.
    Kochendoerfer GG, Chen SY, Mao F, Cressman S, Traviglia S, Shao H, Hunter CL, Low DW, Cagle EN, Carnevali M, Gueriguian V, Keogh PJ, Porter H, Stratton SM, Wiedeke MC, Wilken J, Tang J, Levy JJ, Miranda LP, Crnogorac MM, Kalbag S, Botti P, Schindler-Horvat J, Savatski L, Adamson JW, Kung A, Kent SB, Bradburne JA (2003) Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein. Science 299(5608):884–887Google Scholar
  226. 226.
    Bang D, Chopra N, Kent SB (2004) Total chemical synthesis of crambin. J Am Chem Soc 126(5):1377–1383Google Scholar
  227. 227.
    Luz JG, Yu M, Su Y, Wu Z, Zhou Z, Sun R, Wilson IA (2005) Crystal structure of viral macrophage inflammatory protein I encoded by Kaposi’s sarcoma-associated herpesvirus at 1.7A. J Mol Biol 352(5):1019–1028Google Scholar
  228. 228.
    Sohma Y, Pentelute BL, Whittaker J, Hua Q-X, Whittaker LJ, Ma W, Kent SBH (2008) Comparative properties of insulin-like growth factor 1 (IGF-1) and [Gly7D-Ala]IGF-1 prepared by total chemical synthesis. Angew Chem Int Ed 47:1102–1106Google Scholar
  229. 229.
    Bang D, Tereshko V, Kossiakoff AA, Kent SB (2009) Role of a salt bridge in the model protein crambin explored by chemical protein synthesis: X-ray structure of a unique protein analogue, [V15A]crambin-alpha-carboxamide. Mol Biosyst 5(7):750–756Google Scholar
  230. 230.
    Chiche L, Gaboriaud C, Heitz A, Mornon JP, Castro B, Kollman PA (1989) Use of restrained molecular dynamics in water to determine three-dimensional protein structure: prediction of the three-dimensional structure of Ecballium elaterium trypsin inhibitor II. Proteins 6(4):405–417Google Scholar
  231. 231.
    Heitz A, Chiche L, Le-Nguyen D, Castro B (1989) 1H 2D NMR and distance geometry study of the folding of Ecballium elaterium trypsin inhibitor, a member of the squash inhibitors family. Biochemistry 28(6):2392–2398Google Scholar
  232. 232.
    Patek M, Lebl M (1990) A safety-catch type of amide protecting group. Tetrahedron Lett 31(36):5209–5212Google Scholar
  233. 233.
    Matsueda GR, Stewart JM (1981) A p-methylbenzhydrylamine resin for improved solid-phase synthesis of peptide amides. Peptides 2(1):45–50Google Scholar
  234. 234.
    Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389(6648):251–260Google Scholar
  235. 235.
    Wan Q, Danishefsky SJ (2007) Free-radical-based, specific desulfurization of cysteine: a powerful advance in the synthesis of polypeptides and glycopolypeptides. Angew Chem Int Ed 46(48):9248–9252Google Scholar
  236. 236.
    Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y, Seki N, Suzuki H, Kurihara H, Sakashita H, Takeuchi M, Fujita S, Yamada T, Tanaka A (2001) Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography. J Med Chem 44(4):540–547Google Scholar
  237. 237.
    Sasaki K, Aubry S, Crich D (2011) Chemistry with and around thioacids. Phosphorus Sulfur Silicon 186:1005–1018Google Scholar
  238. 238.
    Pira SL, Boll E, Melnyk O (2013) Synthesis of peptide thioacids at neutral pH using bis(2-sulfanylethyl)amido peptide precursors. Org Lett 15(20):5346–5349Google Scholar
  239. 239.
    Fecourt F, Delpech B, Melnyk O, Crich D (2013) Se-(9-Fluorenylmethyl) selenoesters; preparation, reactivity, and use as convenient synthons for selenoacids. Org Lett 15(14):3758–3761Google Scholar
  240. 240.
    Wang P, Danishefsky SJ (2010) Promising general solution to the problem of ligating peptides and glycopeptides. J Am Chem Soc 132(47):17045–17051Google Scholar
  241. 241.
    Hou W, Zhang X, Li F, Liu CF (2011) Peptidyl N, N-bis(2-mercaptoethyl)-amides as thioester precursors for native chemical ligation. Org Lett 13:386–389Google Scholar
  242. 242.
    Zheng J-S, Tang S, Huang Y-C, Liu L (2013) Development of new thioester equivalents for protein chemical synthesis. Acc Chem Res 46:2475–2484Google Scholar
  243. 243.
    Melnyk O, Agouridas V (2014) From protein total synthesis to peptide transamidation and metathesis: playing with the reversibility of N, S-acyl or N, Se-acyl migration reactions. Curr Opin Chem Biol 22:137–145Google Scholar
  244. 244.
    Melnyk O, Agouridas V (2014) Perhydro-1,2,5-dithiazepine. e-ROS. doi: 10.1002/9780470842898.rn9780470801723
  245. 245.
    Ollivier N, Raibaut L, Blanpain A, Desmet R, Dheur J, Mhidia R, Boll E, Drobecq H, Pira SL, Melnyk O (2014) Tidbits for the synthesis of bis(2-sulfanylethyl)amido (SEA) polystyrene resin, SEA peptides and peptide thioesters. J Pept Sci 20(2):92–97Google Scholar
  246. 246.
    Dheur J, Ollivier N, Vallin A, Melnyk O (2011) Synthesis of peptide alkylthioesters using the intramolecular N, S-acyl shift properties of bis(2-sulfanylethyl)amido peptides. J Org Chem 76(9):3194–3202Google Scholar
  247. 247.
    Dheur J, Ollivier N, Melnyk O (2011) Synthesis of thiazolidine thioester peptides and acceleration of native chemical ligation. Org Lett 13(6):1560–1563Google Scholar
  248. 248.
    Raibaut L, Seeberger P, Melnyk O (2013) Bis(2-sulfanylethyl)amido peptides enable native chemical ligation at proline and minimize deletion side-product formation. Org Lett 15(21):5516–5519Google Scholar
  249. 249.
    Raibaut L, Vicogne J, Leclercq B, Drobecq H, Desmet R, Melnyk O (2013) Total synthesis of biotinylated N domain of human hepatocyte growth factor. Bioorg Med Chem 21(12):3486–3494Google Scholar
  250. 250.
    Agard NJ, Prescher JA, Bertozzi CR (2004) A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. J Am Chem Soc 126(46):15046–15047Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Laurent Raibaut
    • 1
  • Ouafâa El Mahdi
    • 2
  • Oleg Melnyk
    • 1
    Email author
  1. 1.Institut Pasteur de LilleUMR CNRS 8161, Université de LilleLilleFrance
  2. 2.Université Sidi Mohamed Ben AbdellahFezMorocco

Personalised recommendations