Skip to main content
SpringerLink
Log in

Total Synthesis of Glycosylated Proteins

  • Chapter
  • First Online:
Protein Ligation and Total Synthesis I

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 362))

Abstract

Glycoproteins are an important class of naturally occurring biomolecules which play a pivotal role in many biological processes. They are biosynthesized as complex mixtures of glycoforms through post-translational protein glycosylation. This fact, together with the challenges associated with producing them in homogeneous form, has hampered detailed structure-function studies of glycoproteins as well as their full exploitation as potential therapeutic agents. By contrast, chemical synthesis offers the unique opportunity to gain access to homogeneous glycoprotein samples for rigorous biological evaluation. Herein, we review recent methods for the assembly of complex glycopeptides and glycoproteins and present several examples from our laboratory towards the total chemical synthesis of clinically relevant glycosylated proteins that have enabled synthetic access to full-length homogeneous glycoproteins.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Walsh G, Jefferis R (2006) Nat Biotechnol 24:1241

    CAS  Google Scholar 

  2. Apweiler R, Hermjakob J, Sharon N (1999) BBA-Gen Subj 1473:4

    CAS  Google Scholar 

  3. Dwek RA (1996) Chem Rev 96:683

    CAS  Google Scholar 

  4. Varki A (1993) Glycobiology 3:97

    CAS  Google Scholar 

  5. Ohtsubo K, Marth JD (2006) Cell 126:855

    CAS  Google Scholar 

  6. Miller LH, Good MF, Milon G (1994) Science 264:1878

    CAS  Google Scholar 

  7. Dube DH, Bertozzi CR (2005) Nat Rev Drug Discov 4:477

    CAS  Google Scholar 

  8. Hudak JE, Bertozzi CR (2014) Chem Biol 21:16

    CAS  Google Scholar 

  9. Dalziel M, Crispin M, Scanlan CN, Zitzmann N, Dwek RA (2014) Science 343:1235681

    Google Scholar 

  10. Bosques CJ, Tschampel SM, Woods RJ, Imperiali B (2004) J Am Chem Soc 126:8421

    CAS  Google Scholar 

  11. Imperiali B, O′Connor SE (1999) Curr Opin Chem Biol 3:643

    CAS  Google Scholar 

  12. Wormald MR, Petrescu AJ, Pao YL, Glithero A, Elliott T, Dwek RA (2002) Chem Rev 102:371

    CAS  Google Scholar 

  13. Li H, d’Anjou M (2009) Curr Opin Biotechnol 20:678

    CAS  Google Scholar 

  14. Spiro RG (2002) Glycobiology 12:43R

    CAS  Google Scholar 

  15. Rudd PM, Dwek RA (1997) Crit Rev Biochem Mol Biol 32:1

    CAS  Google Scholar 

  16. Rich JR, Wither SG (2009) Nat Chem Biol 5:206

    CAS  Google Scholar 

  17. Bertozzi CR, Kiessling LL (2001) Science 291:2357

    CAS  Google Scholar 

  18. Hojo H, Nakahara Y (2007) Biopolymers 88:308

    CAS  Google Scholar 

  19. Buskas T, Ingale S, Boons GJ (2006) Glycobiology 16:113R

    CAS  Google Scholar 

  20. Merrifield RB (1963) J Am Chem Soc 85:2149

    CAS  Google Scholar 

  21. Yamamoto N, Ohmori Y, Sakakibara T, Sasaki K, Juneja LR, Kajihara Y (2003) Angew Chem Int Ed 42:2537

    CAS  Google Scholar 

  22. Yamamoto N, Takayanagi A, Yoshino A, Sakakibara T, Kajihara Y (2007) Chem Eur J 13:613

    CAS  Google Scholar 

  23. Mathieux N, Paulsen H, Meldal M, Bock K (1997) J Chem Soc Perkin Trans 1:2359

    Google Scholar 

  24. Herzner H, Reipen T, Schultz M, Kunz H (2000) Chem Rev 100:4495

    CAS  Google Scholar 

  25. Gaidzik N, Westerlind U, Kunz H (2013) Chem Soc Rev 42:4431

    Google Scholar 

  26. Wilson RM, Danishefsky SJ (2013) J Am Chem Soc 135:14462

    CAS  Google Scholar 

  27. Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM, Pathangey LB, Madsen CS, Cohen PA, Gendler SJ, Boons GJ (2012) Proc Natl Acad Sci U S A 109:261

    CAS  Google Scholar 

  28. Cohen-Anisfeld ST, Lansbury PT (1993) J Am Chem Soc 115:10531

    CAS  Google Scholar 

  29. Bodanszky M, Natarajan S (1975) J Org Chem 40:2495

    CAS  Google Scholar 

  30. Wang P, Aussedat B, Vohra Y, Danishefsky SJ (2012) Angew Chem Int Ed 51:11571

    CAS  Google Scholar 

  31. Ullmann V, Rädisch M, Boos I, Freund J, Pöhner C, Schwarzinger S, Unverzagt C (2012) Angew Chem Int Ed 51:11566

    CAS  Google Scholar 

  32. Aussedat B, Vohra Y, Park PK, Fernández-Tejada A, Alam SM, Dennison SM, Jaeger FH, Anasti K, Stewart S, Blinn JH, Liao HX, Sodroski JG, Haynes BF, Danishefsky SJ (2013) J Am Chem Soc 135:13113

    CAS  Google Scholar 

  33. Payne RJ, Wong CH (2010) Chem Comm 46:21

    CAS  Google Scholar 

  34. Dawson P, Muir T, Clark-Lewis I, Kent SBH (1994) Science 266:776

    CAS  Google Scholar 

  35. Muir TW (2003) Annu Rev Biochem 72:249

    CAS  Google Scholar 

  36. Macmillan D, Bertozzi CR (2004) Angew Chem Int Ed 43:1355

    CAS  Google Scholar 

  37. Kent SBH (2009) Chem Soc Rev 38:338

    CAS  Google Scholar 

  38. Unverzagt C, Kajihara Y (2013) Chem Soc Rev 42:4408

    CAS  Google Scholar 

  39. Shin Y, Winans KA, Backes BJ, Kent SBH, Ellman JA, Bertozzi CR (1999) J Am Chem Soc 121:11684

    CAS  Google Scholar 

  40. Marcaurelle LA, Mizoue LS, Wilken J, Oldham L, Kent SB, Handel TM, Bertozzi CR (2001) Chem Eur J 7:1129

    CAS  Google Scholar 

  41. Mezzato S, Schaffrath M, Unverzagt C (2005) Angew Chem Int Ed 44:1650

    CAS  Google Scholar 

  42. Yamamoto N, Tanabe Y, Okamoto R, Dawson PE, Kajihara Y (2008) J Am Chem Soc 130:501

    CAS  Google Scholar 

  43. Mende F, Seitz O (2011) Angew Chem Int Ed 50:1232

    CAS  Google Scholar 

  44. Kan C, Danishefsky SJ (2009) Tetrahedron 65:9047

    CAS  Google Scholar 

  45. Yuan Y, Chen J, Wan Q, Wilson RM, Danishefsky SJ (2010) Biopolymers 94:373

    CAS  Google Scholar 

  46. Warren JD, Miller JS, Keding SJ, Danishefsky SJ (2004) J Am Chem Soc 126:6576

    CAS  Google Scholar 

  47. Wan Q, Chen J, Yuan Y, Danishefsky SJ (2008) J Am Chem Soc 130:15814

    CAS  Google Scholar 

  48. Yuan Y, Chen J, Wan Q, Tan Z, Chen G, Kan C, Danishefsky SJ (2009) J Am Chem Soc 131:5432

    CAS  Google Scholar 

  49. Haase C, Seitz O (2008) Angew Chem Int Ed 47:1553

    CAS  Google Scholar 

  50. Macmillan D, Anderson DW (2004) Org Lett 6:4659

    CAS  Google Scholar 

  51. Wu B, Chen J, Warren JD, Chen G, Hua Z, Danishefsky SJ (2006) Angew Chem Int Ed 45:4116

    CAS  Google Scholar 

  52. Yan LZ, Dawson PE (2001) J Am Chem Soc 123:526

    CAS  Google Scholar 

  53. Pentelute BL, Kent SBH (2007) Org Lett 9:687

    CAS  Google Scholar 

  54. González A, Valencia G (1998) Tetrahedron Asymmetry 9:2761

    Google Scholar 

  55. Wan Q, Danishefsky SJ (2007) Angew Chem Int Ed 46:9248

    CAS  Google Scholar 

  56. Shang S, Tan Z, Danishefsky SJ (2011) Proc Natl Acad Sci U S A 108:5986

    CAS  Google Scholar 

  57. Dong S, Shang S, Li J, Tan Z, Dean T, Maeda A, Gardella TJ, Danishefsky SJ (2012) J Am Chem Soc 134:15122

    CAS  Google Scholar 

  58. Li J, Dong S, Townsend SD, Dean T, Gardella TJ, Danishefsky SJ (2012) Angew Chem Int Ed 51:12263

    CAS  Google Scholar 

  59. Brailsford JA, Danishefsky SJ (2012) Proc Natl Acad Sci U S A 109:7196

    CAS  Google Scholar 

  60. Chen J, Wan Q, Yuan Y, Zhu J, Danishefsky SJ (2008) Angew Chem Int Ed 47:8521

    CAS  Google Scholar 

  61. Haase C, Rohde H, Seitz O (2008) Angew Chem Int Ed 47:6807

    CAS  Google Scholar 

  62. Chen J, Wang P, Zhu J, Wan Q, Danishefsky SJ (2010) Tetrahedron 66:2277

    CAS  Google Scholar 

  63. Harpaz Z, Siman P, Kumar KSA, Brik A (2010) ChemBioChem 11:1232

    CAS  Google Scholar 

  64. Tan Z, Shang S, Danishefsky SJ (2010) Angew Chem Int Ed 49:9500

    CAS  Google Scholar 

  65. Yang R, Pasunooti KK, Li F, Liu X-W, Liu C-F (2009) J Am Chem Soc 131:13592

    CAS  Google Scholar 

  66. Ajish Kumar KS, Haj-Yahya M, Olschewski D, Lashuel HA, Brik A (2009) Angew Chem Int Ed 48:8090

    CAS  Google Scholar 

  67. Shang S, Tan Z, Dong S, Danishefsky SJ (2011) J Am Chem Soc 133:10784

    CAS  Google Scholar 

  68. Townsend SD, Tan Z, Dong S, Shang S, Brailsford JA, Danishefsky SJ (2012) J Am Chem Soc 134:3912

    CAS  Google Scholar 

  69. Crich D, Banerjee A (2007) J Am Chem Soc 129:10064

    CAS  Google Scholar 

  70. Tam JP, Yu Q (1998) Biopolymers 46:319

    CAS  Google Scholar 

  71. Saporito A, Marasco D, Chambery A, Botti P, Monti SM, Pedone C, Ruvo M (2006) Biopolymers 83:508

    CAS  Google Scholar 

  72. Okamoto R, Kajihara Y (2008) Angew Chem Int Ed 47:5402

    CAS  Google Scholar 

  73. Malins LR, Cergol KM, Payne RJ (2013) ChemBioChem 14:559

    CAS  Google Scholar 

  74. Thompson RE, Chan B, Radom L, Jolliffe KA, Payne RJ (2013) Angew Chem Int Ed 52:9723

    CAS  Google Scholar 

  75. Malins LR, Cergol KM, Payne RJ (2014) Chem Sci 5:260

    CAS  Google Scholar 

  76. Cergol KM, Thompson RE, Malins LR, Turner P, Payne RJ (2014) Org Lett 16:290

    CAS  Google Scholar 

  77. Nagorny P, Fasching B, Li X, Chen G, Aussedat B, Danishefsky SJ (2009) J Am Chem Soc 131:5792

    CAS  Google Scholar 

  78. Zhang YM, Mallet JM, Sinaÿ P (1992) Carbohydr Res 236:73

    CAS  Google Scholar 

  79. Likhosherstov LM, Novikova OS, Derevitskaja VA, Kochetkov NK (1986) Carbohydr Res 146:C1

    CAS  Google Scholar 

  80. Sakakibara S (1995) Biopolymers 37:17

    CAS  Google Scholar 

  81. Aussedat B, Fasching B, Johnston E, Sane N, Nagorny P, Danishefsky SJ (2012) J Am Chem Soc 134:3532

    CAS  Google Scholar 

  82. Howles CM (1996) Hum Reprod Update 2:172

    CAS  Google Scholar 

  83. Pang SC (2005) Womens Health 1:87

    CAS  Google Scholar 

  84. Nagorny P, Sane N, Fasching B, Aussedat B, Danishefsky SJ (2012) Angew Chem Int Ed 51:975

    CAS  Google Scholar 

  85. Stenman UH, Tiitinen A, Alfthan H, Valmu L (2006) Hum Reprod Update 12:769

    CAS  Google Scholar 

  86. Talwar GP, Vyas HK, Purswani S, Gupta JC (2009) J Reprod Immunol 83:158

    CAS  Google Scholar 

  87. Iversen PL, Mourich DV, Moulton HM (2003) Curr Opin Mol Ther 5:156

    CAS  Google Scholar 

  88. Valmu L, Alfthan H, Hotakainen K, Birken S, Stenman UH (2006) Glycobiology 16:1207

    CAS  Google Scholar 

  89. Fernández-Tejada A, Vadola PA, Danishefsky SJ (2014) J Am Chem Soc 136:8450

    Google Scholar 

  90. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HS, Das G, Devadas S (2006) Cell Res 16:126

    CAS  Google Scholar 

  91. Zhang Q, Johnston EV, Shieh J-H, Moore MAS, Danishefsky SJ (2014) Proc Natl Acad Sci U S A 111:2885

    CAS  Google Scholar 

  92. Krantz SB (1991) Blood 77:419

    CAS  Google Scholar 

  93. Lacombe C, Mayeux P (1998) Haematologica 83:724

    CAS  Google Scholar 

  94. Koury MJ (2005) Exp Hematol 33:1263

    CAS  Google Scholar 

  95. Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A, Wiebe N, Klarenbach S (2009) CMAJ 180:E62

    Google Scholar 

  96. Mattio M, Ceaglio N, Oggero M, Perotti N, Amadeo I, Orozco G, Forno G, Kratje R, Etcheverrigaray M (2011) Biotechnol Prog 27:1018

    CAS  Google Scholar 

  97. Higuchi M, Oh-eda M, Kuboniwa H, Tomonoh K, Shimonaka Y, Ochi N (1992) J Biol Chem 267:7703

    CAS  Google Scholar 

  98. Wang P, Dong S, Brailsford JA, Iyer K, Townsend S, Zhang Q, Hendrickson RC, Shieh JH, Moore MAS, Danishefsky SJ (2012) Angew Chem Int Ed 51:11576

    CAS  Google Scholar 

  99. Schwarz JB, Kuduk SD, Chen X-T, Sames D, Glunz PW, Danishefsky SJ (1999) J Am Chem Soc 121:2662

    CAS  Google Scholar 

  100. Bang D, Pentelute BL, Kent SBH (2006) Angew Chem Int Ed 45:3985

    CAS  Google Scholar 

  101. Wang P, Dong S, Shieh J-H, Peguero E, Hendrickson R, Moore MAS, Danishefsky SJ (2013) Science 342:1357

    CAS  Google Scholar 

  102. Takeuchi M, Inoue N, Strickland TW, Kubota M, Wada M, Shimizu R, Hoshi S, Kozutsumi H, Takasaki S, Kobata A (1989) Proc Natl Acad Sci U S A 86:7819

    CAS  Google Scholar 

  103. Kochendoerfer GG, Chen S-Y, 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, Crnogoran MM, Kalbag S, Potti P, Schindler-Horvat J, Savatski L, Adamson JW, Kung A, Kent SBH, Bradburne JA (2003) Science 299:884

    CAS  Google Scholar 

  104. Hamilton SR, Davidson RC, Sethuraman N, Nett JH, Jiang Y, Rios S, Bobrowicz P, Stadheim TA, Li H, Choi B-K, Hopkins D, Wischnewski H, Roser J, Mitchell T, Strawbridge RR, Hoopes J, Wildt S, Gerngross TU (2006) Science 313:1441

    CAS  Google Scholar 

  105. Sanz-Nebot V, Benavente F, Vallverdú A, Guzman NA, Barbosa J (2003) Anal Chem 75:5220

    CAS  Google Scholar 

  106. Harazono A, Hashii N, Kuribayashi R, Nakazawa S, Kawasaki N (2013) J Pharm Biomed Anal 87:65

    Google Scholar 

  107. Chalker JM, Bernardes GJ, Davis BG (2011) Acc Chem Res 44:730

    CAS  Google Scholar 

  108. Wang LX, Lomino JV (2012) ACS Chem Biol 7:110

    CAS  Google Scholar 

  109. Wang LX, Amin MN (2014) Chem Biol 21:51

    Google Scholar 

  110. Wang L, Schultz PG (2005) Angew Chem Int Ed 44:34

    CAS  Google Scholar 

  111. Liu L, Bennett CS, Wong CH (2006) Chem Comm 42:21

    CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Institutes of Health, William and Alice Goodwin and the Commonwealth Foundation for Cancer Research for generous financial support. AF-T gratefully acknowledges the European Commission (Marie Curie International Outgoing Fellowship) for funding. We acknowledge our colleagues of the Danishefsky laboratory whose work is presented in this manuscript. We thank Professors Yasuhiro Kajihara and Carlo Unverzagt for provocative exchanges and, particularly, for citing precedence on the feasibility of obtaining informative mass spectra of related EPO structures. We thank Rebecca Wilson for assistance in the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Laboratory for Bioorganic Chemistry, Molecular Pharmacology and Chemistry Program, 1275 York Avenue, New York, NY, 10065, USA

    Alberto Fernández-Tejada, John Brailsford, Qiang Zhang & Samuel J. Danishefsky

  2. Chemical and Physical Biology, CIB-CSIC, Ramiro de Maeztu 9, Madrid, 28040, Spain

    Alberto Fernández-Tejada

  3. Cell Biology Program, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY, 10065, USA

    Jae-Hung Shieh & Malcolm A. S. Moore

Authors
  1. Alberto Fernández-Tejada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Brailsford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae-Hung Shieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malcolm A. S. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samuel J. Danishefsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alberto Fernández-Tejada or Samuel J. Danishefsky .

Editor information

Editors and Affiliations

  1. Department of Chemistry, Tsinghua University, Beijing, China

    Lei Liu

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fernández-Tejada, A., Brailsford, J., Zhang, Q., Shieh, JH., Moore, M.A.S., Danishefsky, S.J. (2014). Total Synthesis of Glycosylated Proteins. In: Liu, L. (eds) Protein Ligation and Total Synthesis I. Topics in Current Chemistry, vol 362. Springer, Cham. https://doi.org/10.1007/128_2014_622

Download citation

Publish with us

Policies and ethics

Search

Navigation