Skip to main content
SpringerLink
Log in

Protein recognition using synthetic surface-targeted agents

  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

The design of synthetic agents to disrupt protein-protein interactions has received relatively little attention in recent years. In this review we describe strategies for targeting different types of protein surfaces using mimetics of protein secondary or tertiary structure. In this way strong and selective binding to a protein surface has be achieved and disruption of clinically important protein-protein interactions has been demonstrated in models of human disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Weber, P. C., Ohlendorf, D. H., Wendoloski, J. J. and Salemme, F. R., Structural origins of high-affinity biotin binding to streptavidin, Science, 243 (1989) 85.

    PubMed  Google Scholar 

  2. Buckle, A. M., Schreiber, G. and Fersht, A. R., Protein-protein interaction — Crystal structure analysis of a barnase-barstar complex at 2.0-angstrom resolution, Biochemistry, 3 (1994) 8878–8889.

    Google Scholar 

  3. Blokzul, W. and Engberts, J. B. F. N., Hydrophobic effects-opinions and facts, Angew. Chem. Int. Ed. Engl., 32 (1993) 1545–1579.

    Google Scholar 

  4. Southall, N. T., Dill, K. A. and Haymet A. D. J., A view of the hydrophobic effect, J. Phys. Chem. B, 106 (2002) 521–533.

    Google Scholar 

  5. Dervan, P. B., Molecular recognition of DNA by small molecules, Bioorg. Med. Chem., 9 (2001) 2215–2235.

    PubMed  Google Scholar 

  6. Fan, E., Zhang, Z., Minke, W. E., Hou, Z., Verlinde, C. L. M. J. and Hol, W. G. J., High-affinity pentavalent ligands of Escherichia coli heat-labile enterotoxin by modular structure-based design, J.Am. Chem. Soc., 122 (2000) 2663–2664.

    Google Scholar 

  7. Mammen, M., Choi, S. K. and Whitesides, G. M. Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors, Angew. Chemie. Int. Ed., 37 (1998) 2754–2794.

    Google Scholar 

  8. Cochran, A. G., Protein-protein interfaces: Mimics and inhibitors, Curr. Opin. Chem. Biol., 5 (2001) 654–659. (b) Chmielewski, J., Zutshi, R. and Brickner, M., Inhibiting the assembly of protein-protein interfaces, Curr. Opin. Chem. Biol., 2 (1998) 62–66.

    PubMed  Google Scholar 

  9. Toogood, P. L., Inhibition of protein-protein association by small molecules: Approaches and progress, J. Med. Chem., 45 (2002) 1543–1558.

    PubMed  Google Scholar 

  10. Chothia, C. and Janin, J., Principles of protein-protein recognition, Nature, 256 (1975) 705–708. (b) Jones, S. and Thornton, J. M., Principles of protein-protein interactions, Proc. Natl. Acad. Sci. USA, 93 (1996) 13–20. (c) Le Conte, L., Chothia, C. and Janin, J., Atomic structure of protein-protein recognition sites, J. Mol. Biol., 285 (1999) 2177–2198.

    PubMed  Google Scholar 

  11. Stites, W. E., Protein-protein interactions: Interface structure, binding thermodynamics, and mutational analysis, Chem. Rev., 97 (1997) 1233–1250.

    PubMed  Google Scholar 

  12. Bogan, A. A. and Thorn, K. S., Anatomy of hot spots in protein interfaces, J. Mol. Biol., 280 (1998) 1–9. (b) Clackson, T. and Wells, J. A., A hot-spot of binding-energy in a hormone-receptor interface, Science, 267 (1995) 383–386.

    PubMed  Google Scholar 

  13. Erlanson, D. A., Braisted, A. C., Raphael, D. R., Randal, M., Stroud, R. M., Gordon, E. M. and Wells, J. A., Site-directed ligand discovery, Proc. Natl. Acad. Sci. USA, 97 (2000) 9367–9372. (b) Hajduk, P. J., Bures, M., Praestgaard, J. and Fesik, S. W., Privileged molecules for protein binding identified from NMR-based screening, J. Med. Chem., 43 (2000) 3443–3447. (c) DeLano, W. L., Unraveling hot spots in binding interfaces: Progress and challenges, Curr. Opin. Struct. Biol., 12 (2002) 14–20.

    PubMed  Google Scholar 

  14. Ojwong, J. O. and Rando R. F. et al., T30177 an oligonucleotide stabilized by a intramolecular guanosine octet, is a potent inhibitor of laboratory strains and clinical isolates of human immunodeficiency virus type I, Anti Microb. Agents Chemother., 39 (1995) 2426–2435. (b) Capila, I. and Linhardt, R. J., Heparin — Protein interactions, Angew. Chem. Int. Ed., 41 (2002) 391–412.

    Google Scholar 

  15. Petitou, M., Herault, L. P., Bernat, A., Driguez, P. A., Duchaussoy, P., Lormeau, J. C. and Herbert, J.M., Synthesis of thrombin-inhibiting heparin mimetics without side effects, Nature, 398 (1999) 417–422.

    PubMed  Google Scholar 

  16. Peczuh, M. W. and Hamilton, A. D., Peptide and protein recognition by designed molecules, Chem. Rev., 100 (2000) 2479–2493.

    PubMed  Google Scholar 

  17. Ding, W. and Ellestatad, G. A. et al., Novel and specific respiratory syncytial virus inhibitors that target virus fusion, J. Med. Chem., 41 (1998) 2671–2675.

    PubMed  Google Scholar 

  18. Halliday, S.M., Lackman-Smith, C, Bader, J. P., Rice, W. G., Clanton, D. J., Zalkow, L. H., Buckheit Jr., R. W., Inhibition of human immunodeficiency virus replication by the sulfonated stilbene dye resobene, Antiviral Res., 33 (1996) 41–53.

    PubMed  Google Scholar 

  19. Dezube, B. J. and Crumpacker, C. S., et al., A fusion inhibitor (FP-21399) for the treatment of human immunodeficiency virus infection: A phase I study, J. Infect. Dis., 182 (2000) 607–610.

    PubMed  Google Scholar 

  20. Manetti, F., Cappello, V., Botta, M., Corelli, F., Mongelli, N., Biasoli, G., Lombardi-Borgia, A. and Ciomei, M., Synthesis and binding mode of heterocyclic analogues of suramin inhibiting the human basic fibroblast growth factor, Bioorg. Med. Chem., 6 (1998) 947–958.

    PubMed  Google Scholar 

  21. Zamai, M., Hariharan, C., Pines, D., Safran, M., Yayon, A., Caiolfa, V. R., Cohen-Luria, R., Pines, E. and Parola, A. H., Nature of interaction between basic fibroblast growth factor and the antiangiogenic drug 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolecarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino])-bis-(1,3-napthalene disulfonate) II. Removal of polar interactions affects protein folding, Biophys. J., 82 (2002) 2652–2664.

    PubMed  Google Scholar 

  22. Aviezer, D., Cotton, S., Magda, D., Segev, A., Khasalev, N., Galili, N., Gross, Z. and Yayon, A., Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelial cell proliferation, tumor progression, and metastasis, Cancer Res., 60 (2000) 2973–2980.

    PubMed  Google Scholar 

  23. Berg, T., Cohen, S. B., Desharnais, J., Sonderegger, C., Maslyar, D. J., Goldberg, J., Boger, D. L. and Vogt, P. K., Proc. Natl. Acad. Sci., 99 (2002) 3830–3835.

    PubMed  Google Scholar 

  24. Leung, D. K., Yang, Z. and Breslow, R., Selective disruption of protein aggregation by cyclodextrin dimers, Proc. Natl. Acad. Sci. USA, 97 (2000) 5050–5053.

    PubMed  Google Scholar 

  25. Abul Fazal, M., Roy, B. C., Sun, S., Mallik, S. and Rodgers K. R., Surface recognition of a protein using designed transition metal complexes, J. Am. Chem. Soc., 123 (2001) 6283–6290.

    PubMed  Google Scholar 

  26. Park, H. S., Lin, Q., Hamilton, A. D., Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin, J. Am. Chem. Soc., 121 (1999) 8–13.

    Google Scholar 

  27. Fischer, N. O., McIntosh, C. N., Simard, J. M. and Rotello, V. M., Inhibition of chymotrypsin through surface binding using nanoparticle-based receptors, Proc. Natl. Acad. Sci USA, 99 (2002) 5018–5023.

    PubMed  Google Scholar 

  28. Li, A. P., Screening for human ADME/Tox drug properties in drug discovery, Drug. Discov. Today, 6 (2001) 357–366. (b) Walters, W. P. and Murcko, M. A., Prediction of 'drug-likeness', Adv. Drug Deliver. Rev., 54 (2002) 255–271.

    PubMed  Google Scholar 

  29. Lipinski, C. A., Lombardo, F., Dominy, B. W. and Feeney, P. J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug. Deliver. Rev., 23 (1997) 3–25.

    Google Scholar 

  30. Kabsch, W. and Sander, C., Dictionary of protein secondary structure — Pattern-recognition of hydrogen-bonded and geometrical features, Biopolymers, 22 (1983) 2577–2637.

    PubMed  Google Scholar 

  31. Merutka, G. and Stellwagen, E., Effect of amino acid ion pairs on peptide helicity, Biochemistry, 30 (1991) 1591–1594.

    PubMed  Google Scholar 

  32. Ghadiri, M. R. and Choi, C., Secondary structure nucleation in peptides. Transition metal ion stabilized α-helices, J.Am.Chem. Soc., 112 (1990) 1630–1632. (b) Ruan, F., Chen, Y. and Hopkins, P. B., Metal ion enhanced helicity in synthetic peptides containing unnatural, metal-ligating residues, J. Am. Chem. Soc., 112 (1990) 9403–9404.

    Google Scholar 

  33. Albert, J. A. and Hamilton, A. D., Stabilization of helical domains in short peptides using hydrophobic interactions, Biochemistry, 34 (1995) 984–990.

    PubMed  Google Scholar 

  34. Jackson, D. Y., King, D. S., Chmielewski, J., Singh, S. and Shultz, P. G., General approach to the synthesis of short α-helical peptides, J. Am. Chem. Soc., 113 (1991) 9391–9392.

    Google Scholar 

  35. Osapay, G. and Taylor, J. W., Multicyclic polypeptide model compounds. 2. Synthesis and conformational properties of a highly α-helical uncosapeptide constrained by three side-chain to side-chain lactam bridges, J. Am. Chem. Soc., 114 (1992) 6966–6973.

    Google Scholar 

  36. Yu, C. and Taylor, J. W., Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization, Bioorg. Med. Chem., 7 (1999) 161–175.

    PubMed  Google Scholar 

  37. Cabezas, E. and Satterthwait, A. C., The hydrogen bond mimic approach: Solid-phase synthesis of a peptide stabilized as an α-helix with a hydrazone link, J. Am. Chem. Soc., 121 (1999) 3862–3875.

    Google Scholar 

  38. Schafmeister, C. E., Po, J. and Verdine, G. L., An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides, J. Am. Chem. Soc., 122 (2000) 5891–5892, (b) Blackwell, H. E. and Grubbs, R. H., Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis, Angew. Chem. Int. Ed., 37 (1998) 3281–3284.

    Google Scholar 

  39. Chin, J.W. and Schepartz, A., Design and evolution of a miniature Bcl-2 binding protein, Angew. Chem. Int. Ed., 40 (2001) 3806–3809. (b) Zondlo, N. J. and Schepartz, A., Highly specific DNA recognition by a designed miniature protein, J. Am. Chem. Soc., 121 (1999) 6938–6939. (c) Struthers, M. D., Cheng, R. P. and Imperiali, B., Economy in protein design: Evolution of a metal-independent ββα motif based on the zinc finger domains, J. Am. Chem. Soc., 118 (1996) 3073–3081.

    Google Scholar 

  40. Stigers, K. D., Soth, M. J. and Nowick, J. S., Designed molecules that fold to mimic protein secondary structures, Curr. Opin. Chem. Biol., 3 (1999) 714–723. (b) Gellman, S. H., Foldamers: A manifesto, Acc. Chem. Res., 31 (1998) 173–180.

    PubMed  Google Scholar 

  41. Austin, R. E., Maplestone, R. A., Sefler, A. M., Liu, K., Hruzwicz, W. N., Liu, C. W., Cho, H. S., Wemmer, D. E. and Bartlett, P. A., A template for stabilization of a peptide α-helix: Synthesis and evaluation of conformational effects by circular dichroism and NMR, J. Am. Chem. Soc., 119 (1997) 6461–6472. (b) Kemp, D. S., Allen, T. J., Oslick, S. A. and Boyd, J. G., The structure and energetics of helix formation by short templated peptides in aqueous solution. 2. Characterization of the helical structure of Ac-He11-Ala6-OH, J. Am. Chem. Soc., 118 (1996) 4240–4248.

    Google Scholar 

  42. Nesloney, C. L. and Kelly, J. W., For an example of 2,3′-disubstituted biphenyls as constrained turn mimics see, A 2,3′-substituted biphenyl based amino acid facilitates the formation of monomeric β-hairpin like structure in aqueous solution at elevated temperature, J. Am. Chem. Soc., 118 (1996) 5836–5845.

    Google Scholar 

  43. Jacoby, E., Biphenyls as potential mimetics of protein α-helix, Bioorg. Med. Chem. Lett, 12 (2002) 891–893.

    PubMed  Google Scholar 

  44. Orner, B. P., Ernst, J. T. and Hamilton, A. D., Towards proteomimetics: Terphenyl derivatives as structural and functional mimics of extended regions of an α-helix, J. Am. Chem. Soc., 123 (2001) 5382–5383.

    PubMed  Google Scholar 

  45. Ernst, J. T., Debnath, A. K., Jiang, S., Lu, H. and Hamilton, A. D., Design of a protein surface antagonist based on α-helix mimicry: Inhibition of gp41 assembly and viral fusion, Angew. Chem. Int. Ed., 41 (2002) 278–281.

    Google Scholar 

  46. Kutzki, O., Park, H. S., Ernst, J. T., Orner, B. P., Yin, H. and Hamilton, A. D., Development of a potent Bcl-xL antagonist based on α-helix mimicry, J. Am. Chem. Soc., 124 (2002) 11832–11833.

    Google Scholar 

  47. Sattler, M., Liang, H., Nettesheim, D., Meadows, R. P., Harlin, J. E., Eberstadt, M., Yoon, H. S., Shuker, S. B., Chang, B. S., Minn, A. J., Thompson, C. B. and Fesik, S. W., Structure of Bcl-xL-Bak peptide complex: Recognition between regulators of apoptosis, Science, 275 (1997) 983–986.

    PubMed  Google Scholar 

  48. Larson, T. A., Olson, A. J. and Goodsell, D. S., Morphology of protein-protein interfaces, Chem. Biol., 6 (1998) 421–427.

    Google Scholar 

  49. Odani, S., Komori, and Gejyo, F., Structural analysis of the amyloidogenic kappa Bence Jones protein (FUR), Amyloid, 2 (1999) 77–88.

    Google Scholar 

  50. Scheidig, A., Hynes, T., Pelletier, L. A., Wells, J. A. and Kossiakoff, A. A., Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimers amyloid β-protein precursor and basic pancreatic trypsin inhibitor: Engineering of inhibitors with altered specificities, Prot. Sci., 6 (1997) 1806–1824.

    Google Scholar 

  51. Lin, Q., Park, H. S., Hamuro, Y., Lee, C. S. and Hamilton, A. D., Protein surface recognition by synthetic agents: Design and structural requirements of a family of artificial receptors that bind to cytochrome c, Biopolymers, 47 (1998) 285–298. (b) Jain, R. and Hamilton, A. D., Protein surface recognition by synthetic receptors based on a tetraphenylporphyrin scaffold, Organic Lett., (2000) 1721–1723.

    PubMed  Google Scholar 

  52. Wei, Y., McLendon, G. L., Hamilton, A. D., Case, M. A., Purring, C. B., Lin, Q., Park, H. S., Lee, C. S. and Yu, L., Disruption of proteinprotein interactions: Design of a synthetic receptor that blocks the binding of cytochrome c to cytochrome c peroxidase, J. Chem. Soc. Chem. Commun., (2001) 1580–1581.

  53. Lin, Q. and Hamilton, A. D., Design and synthesis of multiple-loop receptors based on a Calix[4]arene scaffold for protein surface recognition, Comptes Rendues (in press).

  54. Park, H. S., Lin, Q. and Hamilton, A. D., Protein surface recognition by synthetic receptors: A route to novel sub-micromolar inhibitors for chymotrypsin, J. Am. Chem. Soc., 121 (1999) 8–13.

    Google Scholar 

  55. Park, H. S., Lin, Q. and Hamilton, A. D., Modulation of proteinprotein interactions by synthetic receptors: Design of a family of molecules that inhibit serine protease-proteinaceous inhibitor interaction, Proc. Natl. Acad. Sci. USA, 99 (2002) 5105–5109.

    PubMed  Google Scholar 

  56. Oefner, C., Arcy, A. D., Winkler, F. K., Eggimann, B. and Hosang, M., Crystal structure of human platelet derived growth factor, EMBO J., 11 (1992) 3921–3926.

    PubMed  Google Scholar 

  57. Sebti, S. M. and Hamilton, A. D., Design of growth factor antagonists with antiangiogenic and antitumor properties Oncogene, 19 (2000) 6566–6573.

    PubMed  Google Scholar 

  58. Blaskovich, M. A., Lin, Q., Delarue, F. L., Sun, J., Park, H. S., Coppola, D., Hamilton, A. D. and Sebti, S. M., Design of GFB-111 a platelet-derived growth factor binding molecule with anti-angiogenic and anti-cancer activity against human tumors in mice, Nature Biotechnol., 18 (2000) 1065–1070.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, CT, U.S.A

    Rishi Jain, Justin T. Ernst, Olaf Kutzki, Hyung Soon Park & Andrew D. Hamilton

Authors
  1. Rishi Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justin T. Ernst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olaf Kutzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyung Soon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew D. Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew D. Hamilton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jain, R., Ernst, J.T., Kutzki, O. et al. Protein recognition using synthetic surface-targeted agents. Mol Divers 8, 89–100 (2004). https://doi.org/10.1023/B:MODI.0000025652.55320.16

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:MODI.0000025652.55320.16

Search

Navigation