Advertisement

Polypeptide Conjugate Binders for Protein Recognition

  • Lars Baltzer
Chapter
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 277)

Abstract

A new class of hybrid molecules for protein recognition is presented, where polypeptides are covalently linked to small organic molecules to form polypeptide conjugates that bind proteins with high affinity and selectivity. To illustrate the concept, a binder for human carbonic anhydrase II with a dissociation constant of 4 nM is described. The affinity of the polypeptide conjugate arises from cooperativity in binding between a benzenesulfonamide residue, with a dissociation constant of 1.5 μM, and the polypeptide scaffold with a dissociation constant of <1  mM. The combination of a ligand with moderate affinity for a target protein with a polypeptide relaxes considerably the need for high affinity on the part of the polypeptide, and thus the need for structural complexity and preorganization. At the same time, the requirement for high affinity on the part of ligand is relaxed. As a consequence, the time for development of robust, high affinity, selective binder is shortened. The chemical approach to protein recognition provides well-defined molecular entities that are conveniently handled, stored and site-specifically functionalized.

Affinity Conjugate Molecular recognition Polypeptide Protein 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fletcher S, Hamilton AD (2005) Curr Opin Chem Biol 9:632 PubMedCrossRefGoogle Scholar
  2. 2.
    Carter PJ (2006) Nat Rev Immunol 6:343 PubMedCrossRefGoogle Scholar
  3. 3.
    Haab BB (2006) Curr Opin Biotechnol 17:415 PubMedCrossRefGoogle Scholar
  4. 4.
    Ng EWM, Shima DT, Calias P, Emmett T, Cunningham ET Jr, Guyer DR, Adamis AP (2006) Nat Rev Drug Discov 5:123 PubMedCrossRefGoogle Scholar
  5. 5.
    Schlehuber S, Skerra A (2005) Drug Discov Today 10:23 PubMedCrossRefGoogle Scholar
  6. 6.
    Fersht AR (2002) Structure and mechanism in protein science, 4th edn. W.H. Freeman, New York Google Scholar
  7. 7.
    Lyu PC, Gans PJ, Kallenbach NR (1992) J Mol Biol 223:343 PubMedCrossRefGoogle Scholar
  8. 8.
    Fersht AR, Shi JP, Knill Jones J, Lowe DM, Wilkinson AJ, Blow DM, Brick P, Carter P, Waye M, Winter G (1985) Nature 314:235 PubMedCrossRefADSGoogle Scholar
  9. 9.
    Fersht AR, Jackson SE, Serrano L (1993) Phil Trans R Soc London Ser A 345:141 ADSCrossRefGoogle Scholar
  10. 10.
    Page MI, Jencks WP (1971) Proc Natl Acad Sci USA 68:1971 Google Scholar
  11. 11.
    Levinthal C (1968) J Chim Phys 85:44 Google Scholar
  12. 12.
    Taylor PW, King RW, Burgen ASV (1970) Biochemistry 9:2638 PubMedCrossRefGoogle Scholar
  13. 13.
    Liljas A, Håkansson K, Jonsson B-H, Xue YF (1994) Eur J Biochem 219:1 PubMedCrossRefGoogle Scholar
  14. 14.
    Eriksson AE, Kylsten PM, Jones TA, Liljas A (1988) Proteins 4:283 PubMedCrossRefGoogle Scholar
  15. 15.
    Håkansson K, Carlsson M, Svensson LA, Liljas A (1992) J Mol Biol 227:1192 PubMedCrossRefGoogle Scholar
  16. 16.
    Boriack PA, Christianson DW, Kingerywood J, Whitesides GM (1995) J Med Chem 38:2286 PubMedCrossRefGoogle Scholar
  17. 17.
    Venters RA, Farmer BT, Fierke CA, Spicer LD (1996) J Mol Biol 5:1101 CrossRefGoogle Scholar
  18. 18.
    Carlsson U, Jonsson B-H (2000) In: Chegwidden WR, Carter ND, Edwards YH (eds) The carbonic anhydrases: new horizons. Birkhäuser, Basel Google Scholar
  19. 19.
    Krebs HA (1948) Biochem J 43:525 PubMedGoogle Scholar
  20. 20.
    Miller WH, Dessert AM, Roblin RO (1950) J Am Chem Soc 72:4893 CrossRefGoogle Scholar
  21. 21.
    Enander K, Dolphin GT, Andersson LK, Liedberg B, Lundström I, Baltzer L (2002) J Org Chem 67:3120 PubMedCrossRefGoogle Scholar
  22. 22.
    Jain A, Whitesides GM, Alexander RS, Christianson DW (1994) J Med Chem 37:2100 PubMedCrossRefGoogle Scholar
  23. 23.
    Baltzer L, Nilsson H, Nilsson J (2001) Chem Rev 101:3153 PubMedCrossRefGoogle Scholar
  24. 24.
    Andersson LK, Dolphin GT, Baltzer L (2002) Chem Bio Chem 3:741 PubMedGoogle Scholar
  25. 25.
    Olofsson S, Johansson G, Baltzer L (1995) J Chem Soc Perkin Trans 2, p 2047 Google Scholar
  26. 26.
    Andersson LK, Casparsson M, Baltzer L (2002) Chem Eur J 8:3687 CrossRefGoogle Scholar
  27. 27.
    Enander K, Dolphin GT, Liedberg B, Lundström I, Baltzer L (2004) Chem Eur J 10:2375 CrossRefGoogle Scholar
  28. 28.
    Andersson T, Lundquist M, Dolphin GT, Enander K, Jonsson B-H, Nilsson JW, Baltzer L (2005) Chem Biol 12:1245 PubMedCrossRefGoogle Scholar
  29. 29.
    Enander K, Dolphin GT, Baltzer L (2004) J Am Chem Soc 126:4464 PubMedCrossRefGoogle Scholar
  30. 30.
    Becker HC, Lignell M, Enander K, Baltzer L (2005) Abstr Pap Am Chem Soc 230:U2925 Google Scholar
  31. 31.
    Enander K (2003) Folded polypeptide scaffolds for biosensor and biochip applications – design, synthesis, functionalisation and characterisation. Linköping Studies in Science and Technology, Dissertation 848, Linköping Google Scholar
  32. 32.
    Enander K, Aili D, Baltzer L, Lundström I, Liedberg B (2005) Langmuir 21:2480 PubMedCrossRefGoogle Scholar
  33. 33.
    Aili D, Enander K, Rydberg J, Lundström I, Baltzer L, Liedberg B (2006) J Am Chem Soc 128:2194 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  1. 1.Department of Biochemistry and Organic ChemistryUppsala University, BMCUppsalaSweden

Personalised recommendations