Skip to main content
SpringerLink
Log in
Book cover

Chemogenomics pp 123–158Cite as

Chemogenomics with Protein Secondary-Structure Mimetics

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 575))

Summary

During molecular recognition of proteins in biological systems, helices, reverse turns, and β-sheets are dominant motifs. Often there are therapeutic reasons for blocking such recognition sites, and significant progress has been made by medicinal chemists in the design and synthesis of semirigid molecular scaffolds on which to display amino acid side chains. The basic premise is that preorganization of the competing ligand enhances the binding affinity and potential selectivity of the inhibitor. In this chapter, current progress in these efforts is reviewed.

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

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
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

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Pederson, C. J. (1988) The discovery of crown ethers. Angew. Chem. Int. Ed. Engl. 27, 1021–1025.

    Article  Google Scholar 

  2. Cram, D. J. (1988) The design of molecular hosts, guests, and their complexes. Angew. Chem. Int. Ed. Engl. 27, 1009–1020.

    Article  Google Scholar 

  3. Lehn, J.-M. (1988) Supramolecular chemistry – scope and perspectives molecules, supermolecules, and molecular devices. Angew. Chem. Int. Ed. Engl. 27, 89–112.

    Article  Google Scholar 

  4. Fairlie, D. P., West, M. L., and Wong, A. K. (1998) Towards protein surface mimetics. Curr. Med. Chem. 5, 29–62.

    PubMed  CAS  Google Scholar 

  5. Page, M. I., and Jencks, W. P. (1971) Entropic contributions to rate accelerations in enzymic and intramolecular reactions and the chelate effect. Proc. Natl. Acad. Sci. U.S.A. 68, 1678–1683.

    Article  PubMed  CAS  Google Scholar 

  6. Smith, W. W., and Bartlett, P. A. (1998) Macrocyclic inhibitors of penicillopepsin. 3. Design, synthesis, and evaluation of an inhibitor bridged between P2 and P1′. J. Am. Chem. Soc. 120, 4622–4628.

    Article  CAS  Google Scholar 

  7. Murray, C. W., and Verdonk, M. L. (2002) The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J. Comput. Aided Mol. Des. 16, 741–753.

    Article  PubMed  CAS  Google Scholar 

  8. Searle, M. S., and Williams, D. H. (1992) The cost of conformational order: Entropy changes in molecular associations. J. Am. Chem. Soc. 114, 10690–10697.

    Article  CAS  Google Scholar 

  9. Searle, M. S., Williams, D. H., and Gerhard, U. (1992) Partitioning of free energy contributions in the estimation of binding constants: Residual motions and consequences for amide-amide hydrogen strengths. J. Am. Chem. Soc. 114, 10697–10704.

    Article  CAS  Google Scholar 

  10. Sawyer, T. K., Hruby, V. J., Darman, P. S., and Hadley, M. E. (1982) [half-Cys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: A cyclic alpha-melanotropin exhibiting superagonist biological activity. Proc. Natl. Acad. Sci. U.S.A. 79, 1751–1755.

    Article  PubMed  CAS  Google Scholar 

  11. Chang, C. E., Chen, W., and Gilson, M. K. (2007) Ligand configurational entropy and protein binding. Proc. Natl. Acad. Sci. U.S.A. 104, 1534–1539.

    Article  PubMed  CAS  Google Scholar 

  12. Chang, C. E., and Gilson, M. K. (2004) Free energy, entropy, and induced fit in host-guest recognition: Calculations with the second-generation mining minima algorithm. J. Am. Chem. Soc. 126, 13156–13164.

    Article  PubMed  CAS  Google Scholar 

  13. Zeevaart, J. G., Wang, L., Thakur, V. V., Leung, C. S., Tirado-Rives, J., Bailey, C. M., Domaoal, R. A., Anderson, K. S., and Jorgensen, W. L. (2008) Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations. J. Am. Chem. Soc. 130, 9492–9499.

    Article  PubMed  CAS  Google Scholar 

  14. Jorgensen, W. L., and Thomas, L. L. (2008) Perspective on free-energy perturbation calculations for chemical equilibria. J. Chem. Theory Comput. 4, 869–876.

    Article  PubMed  CAS  Google Scholar 

  15. Wang, J., Deng, Y., and Roux, B. (2006) Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials. Biophys. J. 91, 2798–2814.

    Article  PubMed  CAS  Google Scholar 

  16. Lee, M. S., and Olson, M. A. (2006) Calculation of absolute protein-ligand binding affinity using path and endpoint approaches. Biophys. J. 90, 864–877.

    Article  PubMed  CAS  Google Scholar 

  17. Lu, B., and Wong, C. F. (2005) Direct estimation of entropy loss due to reduced translational and rotational motions upon molecular binding. Biopolymers 79, 277–285.

    Article  PubMed  CAS  Google Scholar 

  18. Leavitt, S., and Freire, E. (2001) Direct measurement of protein binding energetics by isothermal titration calorimetry. Curr. Opin. Struct. Biol. 11, 560–566.

    Article  PubMed  CAS  Google Scholar 

  19. Velazquez-Campoy, A., Luque, I., and Freire, E. (2001) The application of thermodynamic methods in drug design. Thermochimica Acta 380, 217–227.

    Article  CAS  Google Scholar 

  20. Velazquez-Campoy, A., Leavitt, S. A., and Freire, E. (2004) Characterization of protein-protein interactions by isothermal titration calorimetry. Methods Mol. Biol. 261, 35–54.

    PubMed  CAS  Google Scholar 

  21. Luque, I., and Freire, E. (2002) Structural parameterization of the binding enthalpy of small ligands. Proteins 49, 181–190.

    Article  PubMed  CAS  Google Scholar 

  22. Freire, E. (2002) Designing drugs against heterogeneous targets. Nat. Biotechnol. 20, 15–16.

    Article  PubMed  CAS  Google Scholar 

  23. Velazquez-Campoy, A., and Freire, E. (2006) Isothermal titration calorimetry to determine association constants for high-affinity ligands. Nat. Protoc. 1, 186–191.

    Article  PubMed  CAS  Google Scholar 

  24. Todd, M. J., Luque, I., Velazquez-Campoy, A., and Freire, E. (2000) Thermodynamic basis of resistance to HIV-1 protease inhibition: Calorimetric analysis of the V82F/I84V active site resistant mutant. Biochemistry 39, 11876–11883.

    Article  PubMed  CAS  Google Scholar 

  25. Velazquez-Campoy, A., Todd, M. J., and Freire, E. (2000) HIV-1 protease inhibitors: Enthalpic versus entropic optimization of the binding affinity. Biochemistry 39, 2201–2207.

    Article  PubMed  CAS  Google Scholar 

  26. Ohtaka, H., Velazquez-Campoy, A., Xie, D., and Freire, E. (2002) Overcoming drug resistance in HIV-1 chemotherapy: The binding thermodynamics of Amprenavir and TMC-126 to wild-type and drug-resistant mutants of the HIV-1 protease. Protein Sci. 11, 1908–1916.

    Article  PubMed  CAS  Google Scholar 

  27. Velazquez-Campoy, A., Muzammil, S., Ohtaka, H., Schon, A., Vega, S., and Freire, E. (2003) Structural and thermodynamic basis of resistance to HIV-1 protease inhibition: Implications for inhibitor design. Curr. Drug Targets Infect. Disord. 3, 311–328.

    Article  PubMed  CAS  Google Scholar 

  28. Muzammil, S., Ross, P., and Freire, E. (2003) A major role for a set of non-active site mutations in the development of HIV-1 protease drug resistance. Biochemistry 42, 631–638.

    Article  PubMed  CAS  Google Scholar 

  29. Schon, A., del Mar Ingaramo, M., and Freire, E. (2003) The binding of HIV-1 protease inhibitors to human serum proteins. Biophys. Chem. 105, 221–230.

    Article  PubMed  CAS  Google Scholar 

  30. Muzammil, S., Armstrong, A. A., Kang, L. W., Jakalian, A., Bonneau, P. R., Schmelmer, V., Amzel, L. M., and Freire, E. (2007) Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J. Virol. 81, 5144–5554.

    Article  PubMed  CAS  Google Scholar 

  31. Li, L., Dantzer, J. J., Nowacki, J., O’Callaghan, B. J., and Meroueh, S. O. (2008) PDBcal: A comprehensive dataset for receptor-ligand interactions with three-dimensional structures and binding thermodynamics from isothermal titration calorimetry. Chem. Biol. Drug Des. 71, 529–532.

    Article  PubMed  CAS  Google Scholar 

  32. Benfield, A. P., Teresk, M. G., Plake, H. R., DeLorbe, J. E., Millspaugh, L. E., and Martin, S. F. (2006) Ligand preorganization may be accompanied by entropic penalties in protein-ligand interactions. Angew. Chem. Int. Ed. Engl. 45, 6830–6835.

    Article  PubMed  CAS  Google Scholar 

  33. Udugamasooriya, D. G., and Spaller, M. R. (2008) Conformational constraint in protein ligand design and the inconsistency of binding entropy. Biopolymers 89, 653–667.

    Article  PubMed  CAS  Google Scholar 

  34. Bastos, M., Pease, J. H., Wemmer, D. E., Murphy, K. P., and Connelly, P. R. (2001) Thermodynamics of the helix-coil transition: Binding of S15 and a hybrid sequence, disulfide stabilized peptide to the S-protein. Proteins 42, 523–530.

    Article  PubMed  CAS  Google Scholar 

  35. Bogan, A. A., and Thorn, K. S. (1998) Anatomy of hot spots in protein interfaces. J. Mol. Biol. 280, 1–9.

    Article  PubMed  CAS  Google Scholar 

  36. Cunningham, B. C., and Wells, J. A. (1993) Comparison of a structural and a functional epitope. J. Mol. Biol. 234, 554–563.

    Article  PubMed  CAS  Google Scholar 

  37. Clackson, T., and Wells, J. A. (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267, 383–386.

    Article  PubMed  CAS  Google Scholar 

  38. Ma, B., and Nussinov, R. (2007) Trp/Met/Phe hot spots in protein-protein interactions: Potential targets in drug design. Curr. Top. Med. Chem. 7, 999–1005.

    Article  PubMed  CAS  Google Scholar 

  39. Sasaki, Y., Murphy, W. A., Heiman, M. L., Lance, V. A., and Coy, D. H. (1987) Solid-phase synthesis and biological properties of psi [CH2NH] pseudopeptide analogues of a highly potent somatostatin octapeptide. J. Med. Chem. 30, 1162–1166.

    Article  PubMed  CAS  Google Scholar 

  40. Pallai, P. V., Struthers, R. S., Goodman, M., Moroder, L., Wunsch, E., and Vale, W. (1985) Partial retro-inverso analogues of somatostatin: Pairwise modifications at residues 7 and 8 and at residues 8 and 9. Biochemistry 24, 1933–1941.

    Article  PubMed  CAS  Google Scholar 

  41. Huang, Z., Probstl, A., Spencer, J. R., Yamazaki, T., and Goodman, M. (1993) Cyclic hexapeptide analogs of somatostatin containing bridge modifications. Syntheses and conformational analyses. Int. J. Pept. Protein Res. 42, 352–365.

    Article  PubMed  CAS  Google Scholar 

  42. Boer, J., Gottschling, D., Schuster, A., Semmrich, M., Holzmann, B., and Kessler, H. (2001) Design and synthesis of potent and selective alpha(4)beta(7) integrin antagonists. J. Med. Chem. 44, 2586–2592.

    Article  PubMed  CAS  Google Scholar 

  43. Hirschmann, R., Hynes, J. Jr., Cichy-Knight, M. A., van Rijn, R. D., Sprengeler, P. A., Spoors, P. G., Shakespeare, W. C., Pietranico-Cole, S., Barbosa, J., Liu, J., Yao, W., Rohrer, S., and Smith, A. B. III (1998) Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis. J. Med. Chem. 41, 1382–1391.

    Article  PubMed  CAS  Google Scholar 

  44. Dudkina, A. S., and Lindsley, C. W. (2007) Small molecule protein-protein inhibitors of the p53-MDM2 interaction. Curr. Top. Med. Chem. 7, 952–960.

    Article  PubMed  CAS  Google Scholar 

  45. Evans, B. E., Rittle, K. E., Bock, M. G., Dipardo, R. M., Freidinger, R. M., Whitter, W. L., Lundell, G. F., Veber, D. F., Anderson, P. S., Chang, R. S. L., Lotti, V. J., Cerino, D. J., Chen, T. B., Kling, P. J., Kunkel, K. A., Springer, J. P., and Hirshfield, J. (1988) Methods for drug discovery - development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 31, 2235–2246.

    Article  PubMed  CAS  Google Scholar 

  46. Ripka, W. C., DeLucca, G. V., Bach, A. C. II, Pottorf, R. S., and Blaney, J. M. (1993) Protein b-turn mimetics I. Design, synthesis, and evaluation in model cyclic peptides. Tetrahedron 49, 3593–3608.

    Article  CAS  Google Scholar 

  47. Ripka, W. C., Lucca, G. V. D., Bach, A. C. II, Pottorf, R. S., and Blaney, J. M. (1993) Protein b-turn mimetics II: Design, synthesis, and evaluation in the cyclic peptide Gramicidin S. Tetrahedron 49, 3609–3628.

    Article  CAS  Google Scholar 

  48. Hata, M., and Marshall, G. R. (2006) Do benzodiazepines mimic reverse-turn structures? J. Comput. Aided Mol. Des. 20, 321–331.

    Article  PubMed  CAS  Google Scholar 

  49. Joseph, C. G., Wilson, K. R., Wood, M. S., Sorenson, N. B., Phan, D. V., Xiang, Z., Witek, R. M., and Haskell-Luevano, C. (2008) The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies. J. Med. Chem. 51, 1423–1431.

    Article  PubMed  CAS  Google Scholar 

  50. Horton, D. A., Bourne, G. T., and Smythe, M. L. (2003) The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev. 103, 893–930.

    Article  PubMed  CAS  Google Scholar 

  51. Patchett, A. A., and Nargund, R. P. (2000) Privileged structures - An update. Annu. Rep. Med. Chem. 35, 289–298.

    Article  CAS  Google Scholar 

  52. Koch, M. A., Schuffenhauer, A., Scheck, M., Wetzel, S., Casaulta, M., Odermatt, A., Ertl, P., and Waldmann, H. (2005) Charting biologically relevant chemical space: A structural classification of natural products (SCONP). Proc. Natl. Acad. Sci. U.S.A. 102, 17272–17277.

    Article  PubMed  CAS  Google Scholar 

  53. Balamurugan, R., Dekker, F. J., and Waldmann, H. (2005) Design of compound libraries based on natural product scaffolds and protein structure similarity clustering (PSSC). Mol. Biosyst. 1, 36–45.

    Article  PubMed  CAS  Google Scholar 

  54. Schuffenhauer, A., Ertl, P., Roggo, S., Wetzel, S., Koch, M. A., and Waldmann, H. (2007) The scaffold tree-visualization of the scaffold universe by hierarchical scaffold classification. J. Chem. Inf. Model. 47, 47–58.

    Article  PubMed  CAS  Google Scholar 

  55. Loughlin, W. A., Tyndall, J. D., Glenn, M. P., and Fairlie, D. P. (2004) Beta-strand mimetics. Chem. Rev. 104, 6085–6117.

    Article  PubMed  CAS  Google Scholar 

  56. Tyndall, J. D. A., Pfeiffer, B., Abbenante, G., and Fairlie, D. P. (2005) Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem. Rev. 105, 793–826.

    Article  PubMed  CAS  Google Scholar 

  57. Marshall, G. R. (2001) Peptide interactions with G-protein coupled receptors. Biopolymers 60, 246–277.

    Article  PubMed  CAS  Google Scholar 

  58. Harrison, S. C., and Aggarwal, A. K. (1990) DNA recognition by proteins with the helix-turn-helix motif. Annu. Rev. Biochem. 59, 933–969.

    Article  PubMed  CAS  Google Scholar 

  59. Suzuki, M. (1994) A framework for the DNA-protein recognition code of the probe helix in transcription factors: The chemical and stereochemical rules. Structure 2, 317–326.

    Article  PubMed  CAS  Google Scholar 

  60. Williamson, J. R. (2000) Induced fit in RNA-protein recognition. Nat. Struct. Biol. 7, 834–837.

    Article  PubMed  CAS  Google Scholar 

  61. Ripka, A. S., and Rich, D. H. (1998) Peptidomimetic design. Curr. Opin. Chem. Biol. 2, 441–452.

    Article  PubMed  CAS  Google Scholar 

  62. Hershberger, S. J., Lee, S. G., and Chmielewski, J. (2007) Scaffolds for blocking protein-protein interactions. Curr. Top. Med. Chem. 7, 928–942.

    Article  PubMed  CAS  Google Scholar 

  63. Hirschmann, R., Nicolaou, K. C., Pietranico, S., Leahy, E. M., Salvino, J., Arison, B., Cichy, M. A., Spoors, P. G., Shakespeare, W. C., Sprengeler, P. A., Hamley, P., Smith, A. B., Reisine, T., Raynor, K., Maechler, L., Donaldson, C., Vale, W., Freidinger, R. M., Cascieri, M. R., and Strader, C. D. (1993) De-Novo design and synthesis of somatostatin nonpeptide peptidomimetics utilizing beta-D-glucose as a novel scaffolding. J. Am. Chem. Soc. 115, 12550–12568.

    Article  CAS  Google Scholar 

  64. Hirschmann, R., Hynes, J., Cichy-Knight, M. A., van Rijn, R. D., Sprengeler, P. A., Spoors, P. G., Shakespeare, W. C., Pietranico-Cole, S., Barbosa, J., Liu, J., Yao, W. Q., Rohrer, S., and Smith, A. B. (1998) Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis. J. Med. Chem. 41, 1382–1391.

    Article  PubMed  CAS  Google Scholar 

  65. Olson, G. L., Cheung, H. C., Chiang, E., Madison, V. S., Sepinwall, J., Vincent, G. P., Winokur, A., and Gary, K. A. (1995) Peptide mimetics of thyrotropin-releasing hormone based on a cyclohexane framework: Design, synthesis, and cognition-enhancing properties. J. Med. Chem. 38, 2866–2879.

    Article  PubMed  CAS  Google Scholar 

  66. Rutledge, L. D., Perlman, J. H., Gershengorn, M. C., Marshall, G. R., and Moeller, K. D. (1996) Conformationally restricted TRH analogs - a probe for the pyroglutamate region. J. Med. Chem. 39, 1571–1574.

    Article  PubMed  CAS  Google Scholar 

  67. Chu, W., Perlman, J. H., Gershengorn, M. C., and Moeller, K. D. (1998) Thyrotropin releasing hormone analogs: A building block approach to the construction of tetracyclic peptidomimetics. Bioorg. Med. Chem. Lett. 8, 3093–3096.

    Article  PubMed  CAS  Google Scholar 

  68. Tong, Y., Olczak, J., Zabrocki, J., Gershengorn, M. C., Marshall, G. R., and Moeller, K. D. (2000) Constrained peptidomimetics for TRH: Cis-peptide bond analogs. Tetrahedron 56, 9791–9800.

    Article  CAS  Google Scholar 

  69. Simpson, J. C., Ho, C., Shands, E. F., Gershengorn, M. C., Marshall, G. R., and Moeller, K. D. (2002) Conformationally restricted TRH analogues: Constraining the pyroglutamate region. Bioorg. Med. Chem. 10, 291–302.

    Article  PubMed  CAS  Google Scholar 

  70. Hanessian, S., and Auzzas, L. (2008) The practice of ring constraint in peptidomimetics using bicyclic and polycyclic amino acids. Acc. Chem. Res. 41, 1241–1251.

    Article  PubMed  CAS  Google Scholar 

  71. Rose, G. D., Gierasch, L. M., and Smith, J. A. (1985) Turns in peptides and proteins. Adv. Protein Chem. 37, 1–109.

    Article  PubMed  CAS  Google Scholar 

  72. Frieden, C., Huang, E. S., and Ponder, J. W. (2001) Turn scanning. Experimental and theoretical approaches to the role of turns. Methods Mol. Biol. 168, 133–158.

    PubMed  CAS  Google Scholar 

  73. Tran, T. T., McKie, J., Meutermans, W. D. F., Bourne, G. T., Andrews, P. R., and Smythe, M. L. (2005) Topological side-chain classification of b-turns: Ideal motifs for peptidomimetic development. J. Comput. Aided Mol. Des. 19, 551–566.

    Article  PubMed  CAS  Google Scholar 

  74. Tran, T. T., Kulis, C., Long, S. M., Bryant, D., Adams, P., and Smythe, M. L. (2008) Defining scaffold geometries for interacting with proteins: Geometrical classification of secondary structure linking regions. J. Med. Chem. in press.

    Google Scholar 

  75. Arbor, S., and Marshall, G. R. (2008) A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank. J. Comput. Aided Mol. Des. 23, 87–95.

    Article  PubMed  CAS  Google Scholar 

  76. Deslauriers, R., Leach, S. J., Maxfield, F. R., Minasian, E., McQuie, J. R., Meinwald, Y. C., Némethy, G., Pottle, M. S., Rae, I. D., Scheraga, H. A., Stimson, E. R., and Nispen, J. W. V. (1979) Cyclized dipeptide model for a beta-bend. Proc. Natl. Acad. Sci. U.S.A. 76, 2512–2514.

    Article  PubMed  CAS  Google Scholar 

  77. Sharma, A. K., and Chauhan, V. S. (1988) Analogues of luteinizing hormone-releasing hormone (LH-RH) containing dehydroalanine in 6th position. Int. J. Pept. Protein Res. 31, 225–230.

    Article  PubMed  CAS  Google Scholar 

  78. Fabian, P., Chauhan, V. S., and Pongor, S. (1994) Predicted conformation of poly(dehydroalanine): A preference for turns. Biochim. Biophys. Acta 1208, 89–93.

    Article  PubMed  CAS  Google Scholar 

  79. Pieroni, O., Fissi, A., Jain, R. M., and Chauhan, V. S. (1996) Solution structure of dehydropeptides: A CD investigation. Biopolymers 38, 97–108.

    Article  PubMed  CAS  Google Scholar 

  80. Mathur, P., Ramakumar, S., and Chauhan, V. S. (2004) Peptide design using alpha,beta-dehydro amino acids: From beta-turns to helical hairpins. Biopolymers 76, 150–161.

    Article  PubMed  CAS  Google Scholar 

  81. Patel, H. C., Singh, T. P., Chauhan, V. S., and Kaur, P. (1990) Synthesis, crystal structure, and molecular conformation of peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH. Biopolymers 29, 509–515.

    Article  PubMed  CAS  Google Scholar 

  82. Rajashankar, K. R., Chauhan, V. S., and Ramakumar, S. (1995) Crystal and molecular structure of Boc-Phe-Val-OMe; comparison of the peptide conformation with its dehydro analogue. Int. J. Pept. Protein Res. 46, 487–493.

    Article  PubMed  CAS  Google Scholar 

  83. Rajashankar, K. R., Ramakumar, S., Jain, R. M., and Chauhan, V. S. (1996) Helix termination and chain reversal: Crystal and molecular structure of the alpha, beta-dehydrooctapeptide Boc-Val-DeltaPhe-Phe-Ala-Leu-Ala-DeltaPhe-Leu-OH. J. Biomol. Struct. Dyn. 13, 641–647.

    Article  PubMed  CAS  Google Scholar 

  84. Chalmers, D. K., and Marshall, G. R. (1995) Pro-D-NMe-amino acid and D-Pro-NMe-amino acid: Simple, efficient reverse-turn constraints. J. Am. Chem. Soc. 117, 5927–5937.

    Article  CAS  Google Scholar 

  85. Takeuchi, Y., and Marshall, G. R. (1998) Conformational analysis of reverse-turn constraints by N-methylation and N-hydroxylation of amide bonds in peptides and non-peptide mimetics. J. Am. Chem. Soc. 120, 5363–5372.

    Article  CAS  Google Scholar 

  86. Spath, J., Stuart, F., Jiang, L., and Robinson, J. A. (1998) Stabilization of a b-hairpin conformation in a cyclic peptide using the templating effect of a heterochiral diproline unit. Helv. Chim. Acta 81, 1726–1738.

    Article  Google Scholar 

  87. Davies, J. S. (2003) The cyclization of peptides and depsipeptides. J. Pept. Sci. 9, 471–501.

    Article  PubMed  CAS  Google Scholar 

  88. El Haddadi, M., Cavelier, F., Vives, E., Azmani, A., Verducci, J., and Martinez, J. (2000) All-L-Leu-Pro-Leu-Pro: A challenging cyclization. J. Pept. Sci. 6, 560–570.

    Article  CAS  Google Scholar 

  89. Durani, S. (2008) Protein design with L- and D-amino acid structures as the alphabet. Acc. Chem. Res. 41, 1301–1308.

    Article  PubMed  CAS  Google Scholar 

  90. Marshall, G. R., and Bosshard, H. E. (1972) Angiotensin II. Studies on the biologically active conformation. Circ. Res. 31(Suppl 2), 143–150.

    PubMed  Google Scholar 

  91. Yun, R. H., Anderson, A., and Hermans, J. (1991) Proline in alpha-helix: Stability and conformation studied by dynamics simulation. Proteins 10, 219–228.

    Article  PubMed  CAS  Google Scholar 

  92. Chatterjee, J., Gilon, C., Hoffman, A., and Kessler, H. (2008) N-Methylation of peptides: A new perspective in medicinal chemistry. Acc. Chem. Res. 41, 1331–1342.

    Article  PubMed  CAS  Google Scholar 

  93. Che, Y., and Marshall, G. R. (2006) Impact of cis-proline analogs on peptide conformation. Biopolymers 81, 392–406.

    Article  PubMed  CAS  Google Scholar 

  94. Che, Y., and Marshall, G. R. (2004) Impact of azaproline on peptide conformation. J. Org. Chem. 69, 9030–9042.

    Article  PubMed  CAS  Google Scholar 

  95. Spatola, A. F. (1983) In: Weinstein, B. (ed.) Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins. Marcel Dekker, New York, pp. 267–357.

    Google Scholar 

  96. Spatola, A. F. (1993) Synthesis of pseudopeptides. Meth. Neurosci. 13, 19–42.

    CAS  Google Scholar 

  97. Deechongkit, S., Dawson, P. E., and Kelly, J. W. (2004) Toward assessing the position-dependent contributions of backbone hydrogen bonding to beta-sheet folding thermodynamics employing amide-to-ester perturbations. J. Am. Chem. Soc. 126, 16762–16771.

    Article  PubMed  CAS  Google Scholar 

  98. Deechongkit, S., Nguyen, H., Powers, E. T., Dawson, P. E., Gruebele, M., and Kelly, J. W. (2004) Context-dependent contributions of backbone hydrogen bonding to beta-sheet folding energetics. Nature 430, 101–105.

    Article  PubMed  CAS  Google Scholar 

  99. Blankenship, J. W., Balambika, R., and Dawson, P. E. (2002) Probing backbone hydrogen bonds in the hydrophobic core of GCN4. Biochemistry 41, 15676–15684.

    Article  PubMed  CAS  Google Scholar 

  100. Beligere, G. S., and Dawson, P. E. (2000) Design, synthesis, and characterization of 4-ester CI2, a model for the backbone hydrogen bonding in protein a-helices. J. Am. Chem. Soc. 122, 12079–12082.

    Article  CAS  Google Scholar 

  101. Zabrocki, J., Smith, G. D., Dunbar J. B. Jr., Iijima, H., and Marshall, G. R. (1988) Conformational mimicry. 1. 1,5-disubstituted tetrazole ring as a surrogate for the cis amide bond. J. Am. Chem. Soc. 110, 5875–5880.

    Article  CAS  Google Scholar 

  102. Smith, G. D., Zabrocki, J., Flak, T. A., and Marshall, G. R. (1991) Conformational mimicry. II. An obligatory cis amide bond in a small linear peptide. Int. J. Pept. Protein Res. 37, 191–197.

    Article  PubMed  CAS  Google Scholar 

  103. Zabrocki, J., Dunbar, J. B. Jr., Marshall, K. W., Toth, M. V., and Marshall, G. R. (1992) Conformational mimicry. Part III. Synthesis and incorporation of 1,5-disubstituted tetrazole dipeptide analogs into peptides with preservation of chiral integrity: Bradykinin. J. Org. Chem. 57, 202–209.

    Article  CAS  Google Scholar 

  104. Beusen, D. D., Zabrocki, J., Slomczynska, U., Head, R. D., Kao, J., and Marshall, G. R. (1995) Conformational mimicry: Synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis-amide bond surrogate. Biopolymers 36, 181–200.

    Article  PubMed  CAS  Google Scholar 

  105. Zabrocki, J., and Marshall, G. R. (1999) In: Kazmierski, W. (ed.) Peptidomimetics Protocols. Humana Press, Totowa, pp. 417–436.

    Google Scholar 

  106. Kaczmarek, K., Jankowski, S., Siemion, I. Z., Wieczorek, Z., Benedetti, E., Di Lello, P., Isernia, C., Saviano, M., and Zabrocki, J. (2002) Tetrazole analogues of cyclolinopeptide A: Synthesis, conformation, and biology. Biopolymers 63, 343–357.

    Article  PubMed  CAS  Google Scholar 

  107. Nachman, R. J., Zabrocki, J., Olczak, J., Williams, H. J., Moyna, G., Ian Scott, A., and Coast, G. M. (2002) cis-peptide bond mimetic tetrazole analogs of the insect kinins identify the active conformation. Peptides 23, 709–716.

    Article  PubMed  CAS  Google Scholar 

  108. Taneja-Bageshwar, S., Strey, A., Kaczmarek, K., Zabrocki, J., Pietrantonio, P. V., and Nachman, R. J. (2008) Comparison of insect kinin analogs with cis-peptide bond, type VI-turn motifs identifies optimal stereochemistry for interaction with a recombinant arthropod kinin receptor from the southern cattle tick Boophilus microplus. Peptides 29, 295–301.

    Article  PubMed  CAS  Google Scholar 

  109. Beusen, D. D., Zabrocki, J., Slomczynska, U., Head, R. D., Kao, J. L., and Marshall, G. R. (1995) Conformational mimicry: Synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis amide bond surrogate. Biopolymers 36, 181–200.

    Article  PubMed  CAS  Google Scholar 

  110. Lewis, W. G., Green, L. G., Grynszpan, F., Radic, Z., Carlier, P. R., Taylor, P., Finn, M. G., and Sharpless, K. B. (2002) Click chemistry in situ: Acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew. Chem. Int. Ed. Engl. 41, 1053–1057.

    PubMed  CAS  Google Scholar 

  111. Tornoe, C. W., Christensen, C., and 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, 3057–3064.

    Article  PubMed  CAS  Google Scholar 

  112. Kolb, H. C., and Sharpless, K. B. (2003) The growing impact of click chemistry on drug discovery. Drug Discov. Today 8, 1128–1137.

    Article  PubMed  CAS  Google Scholar 

  113. Zhang, L., Chen, X., Xue, P., Sun, H. H., Williams, I. D., Sharpless, K. B., Fokin, V. V., and Jia, G. (2005) Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc. 127, 15998–15999.

    Article  PubMed  CAS  Google Scholar 

  114. Tornoe, C. W., Sanderson, S. J., Mottram, J. C., Coombs, G. H., and Meldal, M. (2004) Combinatorial library of peptidotriazoles: Identification of [1,2,3]-triazole inhibitors against a recombinant Leishmania mexicana cysteine protease. J. Comb. Chem. 6, 312–324.

    Article  PubMed  CAS  Google Scholar 

  115. Deiters, A., Cropp, T. A., Mukherji, M., Chin, J. W., Anderson, J. C., and Schultz, P. G. (2003) Adding amino acids with novel reactivity to the genetic code of Saccromyces Cerevisiae. J. Am. Chem. Soc. 125, 11782–11783.

    Article  PubMed  CAS  Google Scholar 

  116. Hitotsuyanagi, Y., Motegi, S., Fukaya, H., and Takeya, K. (2002) A cis amide bond surrogate incorporating 1,2,4-triazole. J. Org. Chem. 67, 3266–3271.

    Article  PubMed  CAS  Google Scholar 

  117. Hitotsuyanagi, Y., Motegi, S., Hasuda, T., and Takeya, K. (2004) Semisynthesis of an analogue of antitumor bicyclic hexapeptide RA-VII by fixing the Ala-2/Tyr-3 bond to Cis by incorporating a triazole cis-amide bond surrogate. Org. Lett. 6, 1111–1114.

    Article  PubMed  CAS  Google Scholar 

  118. Bock, V. D., Speijer, D., Hiemstra, H., and van Maarseveen, J. H. (2007) 1,2,3-Triazoles as peptide bond isosteres: Synthesis and biological evaluation of cyclotetrapeptide mimics. Org. Biomol. Chem. 5, 971–975.

    Article  PubMed  CAS  Google Scholar 

  119. Cornille, F., Slomczynska, U., Smythe, M. L., Beusen, D. D., Moeller, K. D., and Marshall, G. R. (1995) Electrochemical cyclization of dipeptides toward novel bicyclic, reverse-turn peptidomimetics.1. Synthesis and conformational analysis of 7,5-bicyclic systems. J. Am. Chem. Soc. 117, 909–917.

    Article  CAS  Google Scholar 

  120. Slomczynska, U., Chalmers, D. K., Cornille, F., Smythe, M. L., Beusen, D. D., Moeller, K. D., and Marshall, G. R. (1996) Electrochemical cyclization of dipeptides to form novel bicyclic, reverse-turn peptidomimetics.2. Synthesis and conformational analysis of 6,5-bicyclic systems. J. Org. Chem. 61, 1198–1204.

    Article  CAS  Google Scholar 

  121. Bourne, G. T., Golding, S. W., McGeary, R. P., Meutermans, W. D., Jones, A., Marshall, G. R., Alewood, P. F., and Smythe, M. L. (2001) The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides. J. Org. Chem. 66, 7706–7713.

    Article  PubMed  CAS  Google Scholar 

  122. Horton, D. A., Bourne, G. T., and Smythe, M. L. (2002) Exploring privileged structures: The combinatorial synthesis of cyclic peptides. Mol. Divers. 5, 289–304.

    Article  PubMed  Google Scholar 

  123. Patgiri, A., Jochim, A. L., and Arora, P. S. (2008) A hydrogen bond surrogate approach for stabilization of short peptide sequences in helical conformation. Acc Chem. Res. 41, 1289–1300.

    Article  PubMed  CAS  Google Scholar 

  124. Che, Y., and Marshall, G. R. (2006) Engineering cyclic tetrapeptides containing chimeric amino acids as preferred reverse-turn scaffolds. J. Med. Chem. 49, 111–124.

    Article  PubMed  CAS  Google Scholar 

  125. Mastle, W., Link, U., Witschel, W., Thewalt, U., Weber, T., and Rothe, M. (1991) Conformation and formation tendency of the cyclotetrapeptide cyclo (D-Pro-D-Pro-L-Pro-L-Pro): Experimental results and molecular modeling studies. Biopolymers 31, 735–744.

    Article  PubMed  CAS  Google Scholar 

  126. Mastle, W., Weber, T., Thewalt, U., and Rothe, M. (1989) Cyclo(D-Pro-L-Pro-D-Pro-L-Pro): Structural properties and cis/trans isomerization of the cyclotetrapeptide backbone. Biopolymers 28, 161–174.

    Article  Google Scholar 

  127. Link, U., Mastle, W., and Rothe, M. (1993) Conformations and conformational interconversions of diastereomeric cyclic tetraprolines. Int. J. Pept. Protein Res. 42, 475–483.

    Article  PubMed  CAS  Google Scholar 

  128. Bats, J. W., Friedrich, A., Fuess, H., Kessler, H., Mastle, W., and Rothe, M. (1979) Boat conformation of cyclo-[L-Pro2-D-Pro]. Angew. Chem. Int. Ed. Engl. 18, 538–539.

    Article  Google Scholar 

  129. Rothe, M., and Mastle, W. (1982) Macrocycles of D- and L-proline residues. Angew. Chem. Int. Ed. Engl. 21, 220–221.

    Article  Google Scholar 

  130. Gilbertson, S. R., and Pawlick, R. V. (1995) The synthesis and conformation of dihydroxy-cyclo(D-Pro-L-Pro-D-Pro-L-Pro). Tetrahedron Lett. 36, 1229–1232.

    Article  CAS  Google Scholar 

  131. Xu, H.-C., and Moeller, K. D. (2008) Intramolecular anodic olefin coupling reactions: The use of a nitrogen trapping group. J. Am. Chem. Soc. 130, 13542–13543.

    Article  PubMed  CAS  Google Scholar 

  132. Arbor, S., Kao, J., Wu, Y., and Marshall, G. R. (2008) c[D-pro-Pro-D-pro-N-methyl-Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse-turns. Biopolymers 90, 384–393.

    Article  PubMed  CAS  Google Scholar 

  133. Ye, Y., Liu, M., Kao, J. L., and Marshall, G. R. (2006) Novel trihydroxamate-containing peptides: Design, synthesis, and metal coordination. Biopolymers 84, 472–489.

    Article  PubMed  CAS  Google Scholar 

  134. Che, Y., Brooks, B. R., Riley, D. P., Reaka, A. J., and Marshall, G. R. (2007) Engineering metal complexes of chiral pentaazacrowns as privileged reverse-turn scaffolds. Chem. Biol. Drug Des. 69, 99–110.

    Article  PubMed  CAS  Google Scholar 

  135. Ye, Y., Liu, M., Kao, J. L., and Marshall, G. R. (2008) Design, synthesis, and metal binding of novel pseudo-oligopeptides containing two phosphinic acid groups. Biopolymers 89, 72–85.

    Article  PubMed  CAS  Google Scholar 

  136. Tian, Z. Q., and Bartlett, P. A. (1996) Metal coordination as a method for templating peptide conformation. J. Am. Chem. Soc. 118, 943–949.

    Article  CAS  Google Scholar 

  137. Shi, Y., and Sharma, S. (1999) Metallopeptide approach to the design of biologically active ligands: Design of specific human neutrophil elastase inhibitors. Bioorg. Med. Chem. Lett. 9, 1469–1474.

    Article  PubMed  CAS  Google Scholar 

  138. Shi, Y., Cai, H.-Z., Yang, W. H., Blood, C., Shadiack, A., and Sharma, S. (1999) in “218th ACS National Meeting”, American Chemical Society, New Orleans, LA.

    Google Scholar 

  139. Reaka, A. J., Ho, C. M., and Marshall, G. R. (2002) Metal complexes of chiral pentaazacrowns as conformational templates for beta-turn recognition. J. Comput. Aided Mol. Des. 16, 585–600.

    Article  PubMed  CAS  Google Scholar 

  140. Riley, D. P. (2000) Rational design of synthetic enzymes and their potential utility as human pharmaceuticals: Development of manganese(II)-based superoxide dismutase mimics. Adv. Supramolecular Chem. 6, 217–244.

    Article  CAS  Google Scholar 

  141. Riley, D. P., Henke, S. L., Lennon, P. J., and Aston, K. (1999) Computer-Aided Design (CAD) of synzymes: Use of molecular mechanics (MM) for the rational design of superoxide dismutase mimics. Inorg. Chem. 38, 1908–1917.

    Article  PubMed  CAS  Google Scholar 

  142. Tamamura, H., Otaka, A., Murakami, T., Ibuka, T., Sakano, K., Waki, M., Matsumoto, A., Yamamoto, N., and Fujii, N. (1996) An anti-HIV peptide, T22, forms a highly active complex with Zn(II). Biochem. Biophys. Res. Commun. 229, 648–652.

    Article  PubMed  CAS  Google Scholar 

  143. Tamamura, H., Xu, Y., Hattori, T., Zhang, X., Arakaki, R., Kanbara, K., Omagari, A., Otaka, A., Ibuka, T., Yamamoto, N., Nakashima, H., and Fujii, N. (1998) A low-molecular-weight inhibitor against the chemokine receptor CXCR4: A strong anti-HIV peptide T140. Biochem. Biophys. Res. Commun. 253, 877–882.

    Article  PubMed  CAS  Google Scholar 

  144. Ye, Y., Liu, M., Kao, J. L., and Marshall, G. R. (2003) Peptide-bond modification for metal coordination: Peptides containing two hydroxamate groups. Biopolymers 71, 489–515.

    Article  PubMed  CAS  Google Scholar 

  145. Akiyama, M., Iesaki, K., Katoh, A., and Shimizu, K. (1986) N-hydroxy amides.5. Synthesis and properties Of N-hydroxypeptides having leucine enkephalin sequences. J. Chem. Soc. Perkin. 1, 851–855.

    Article  Google Scholar 

  146. Tran, T. T., McKie, J., Meutermans, W. D., Bourne, G. T., Andrews, P. R., and Smythe, M. L. (2005) Topological side-chain classification of beta-turns: Ideal motifs for peptidomimetic development. J. Comput. Aided Mol. Des. 19, 551–566.

    Article  PubMed  CAS  Google Scholar 

  147. Blomberg, D., Kreye, P., Fowler, C., Brickmann, K., and Kihlberg, J. (2006) Synthesis and biological evaluation of leucine enkephalin turn mimetics. Org Biomol Chem 4, 416–423.

    Article  PubMed  CAS  Google Scholar 

  148. Blomberg, D., Hedenstrom, M., Kreye, P., Sethson, I., Brickmann, K., and Kihlberg, J. (2004) Synthesis and conformational studies of a beta-turn mimetic incorporated in Leu-enkephalin. J. Org. Chem. 69, 3500–3508.

    Article  PubMed  CAS  Google Scholar 

  149. Hanessian, S., McNaughtonSmith, G., Lombart, H. G., and Lubell, W. D. (1997) Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptide mimetics. Tetrahedron 53, 12789–12854.

    Article  CAS  Google Scholar 

  150. Polyak, F., and Lubell, W. D. (1998) Rigid dipeptide mimics - Synthesis of enantiopure 5- and 7-benzyl and 5,7-dibenzyl indolizidinone amino acids via enolization and alkylation of delta-oxo alpha,omega-di-[N-(9-(9-phenylfluorenyl))amino]azelate esters. J. Org. Chem. 63, 5937–5949.

    Article  PubMed  CAS  Google Scholar 

  151. Gosselin, F., and Lubell, W. D. (2000) Rigid dipeptide surrogates: Syntheses of enantiopure quinolizidinone and pyrroloazepinone amino acids from a common diaminodicarboxylate precursor. J. Org. Chem. 65, 2163–2171.

    Article  PubMed  CAS  Google Scholar 

  152. Halab, L., Gosselin, F., and Lubell, W. D. (2000) Design, synthesis, and conformational analysis of azacycloalkane amino acids as conformationally constrained probes for mimicry of peptide secondary structures. Biopolymers 55, 101–122.

    Article  PubMed  CAS  Google Scholar 

  153. Finn, F. M., and Hofmann, K. (1973) The S-peptide S-protein System: A Model for hormone-receptor interaction. Acc. Chem. Res.6, 169–176.

    Article  CAS  Google Scholar 

  154. Varadarajan, R., Connelly, P. R., Sturtevant, J. M., and Richards, F. M. (1992) Heat capacity changes for protein-peptide interactions in the ribonuclease S System. Biochemistry 31, 1421–1426.

    Article  PubMed  CAS  Google Scholar 

  155. Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., and Pavletich, N. P. (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948–953.

    Article  PubMed  CAS  Google Scholar 

  156. Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N., and Liu, E. A. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848.

    Article  PubMed  CAS  Google Scholar 

  157. Fletcher, S., and Hamilton, A. D. (2007) Protein-protein interaction inhibitors: Small molecules from screening techniques. Curr. Topics Med. Chem. 7, 922–927.

    Article  CAS  Google Scholar 

  158. Garcia-Echeverria, C., Chene, P., Blommers, M. J., and Furet, P. (2000) Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53. J. Med. Chem. 43, 3205–3208.

    Article  PubMed  CAS  Google Scholar 

  159. Chene, P., Fuchs, J., Bohn, J., Garcia-Echeverria, C., Furet, P., and Fabbro, D. (2000) A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J. Mol. Biol. 299, 245–253.

    Article  PubMed  CAS  Google Scholar 

  160. Hodgkin, E. E., Clark, J. D., Miller, K. R., and Marshall, G. R. (1990) Conformational analysis and helical preferences of normal and a,a-dialkyl amino acids. Biopolymers 30, 533–546.

    Article  CAS  Google Scholar 

  161. Pauling, L., Corey, R. B., and Branson, H. R. (1951) The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. Proc. Natl. Acad. Sci. U.S.A. 37, 205–211.

    Article  PubMed  CAS  Google Scholar 

  162. Donohue, J. (1953) Hydrogen bonded helical configurations of the polypeptide chain. Proc. Natl. Acad. Sci. U.S.A. 39, 470–478.

    Article  PubMed  CAS  Google Scholar 

  163. Kuster, D. J., Urahata, S., Ponder, J. W., and Marshall, G. R. (2007) In: Abst 51st Biophysical Soc. Meeting, Poster 1791. The Biophysical Society, Baltimore.

    Google Scholar 

  164. Wieczorek, R., and Dannenberg, J. J. (2004) Comparison of fully optimized a- and 3.10-Helices with extended b-strands. An ONIOM density functional theory study. J. Am. Chem. Soc. 126, 14198–14205.

    Article  PubMed  CAS  Google Scholar 

  165. Ren, P., and Ponder, J. W. (2002) Polarizable atomic multipole water model for molecular mechanics simulation. J. Phys. Chem. B 107, 5933–5947.

    Article  CAS  Google Scholar 

  166. Ren, P., and Ponder, J. W. (2002) Consistent treatment of inter- and intramolecular polarization in molecular mechanics calculations. J. Comput. Chem. 23, 1497–1506.

    Article  PubMed  CAS  Google Scholar 

  167. Ponder, J. W., and Case, D. A. (2003) Force fields for protein simulations. Adv. Protein Chem. 66, 27–85.

    Article  PubMed  CAS  Google Scholar 

  168. Grossfield, A., Ren, P., and Ponder, J. W. (2003) Ion solvation thermodynamics from simulation with a polarizable force field. J. Am. Chem. Soc. 125, 15671–15682.

    Article  PubMed  CAS  Google Scholar 

  169. Best, R. B., Buchete, N.-V., and Hummer, G. (2008) Are current molecular dynamics force fields too helical? Biophys. J. 95, L07–L09.

    Article  PubMed  CAS  Google Scholar 

  170. Cummings, M. D., Schubert, C., Parks, D. J., Calvo, R. R., LaFrance, L. V., Lattanze, J., Milkiewicz, K. L., and Lu, T. (2006) Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction. Chem. Biol. Drug Des. 67, 201–205.

    Article  PubMed  CAS  Google Scholar 

  171. Burgess, A. W., and Leach, S. J. (1973) An obligatory alpha-helical amino acid residue. Biopolymers 12, 2599–2605.

    Article  PubMed  CAS  Google Scholar 

  172. Marshall, G. R., Hodgkin, E. E., Langs, D. A., Smith, G. D., Zabrocki, J., and Leplawy, M. T. (1990) Factors governing helical preference of peptides containing multiple alpha,alpha-dialkyl amino acids. Proc. Natl. Acad. Sci. U.S.A. 87, 487–491.

    Article  PubMed  CAS  Google Scholar 

  173. Smythe, M. L., Huston, S. E., and Marshall, G. R. (1993) Free-energy profile of A 3(10)-helical to alpha-helical transition of an oligopeptide in various solvents. J. Am. Chem. Soc. 115, 11594–11595.

    Article  CAS  Google Scholar 

  174. Bisetty, K., Catalan, J. G., Kruger, H. G., and Perez, J. J. (2005) Conformational analysis of small peptides of the type Ac-X-NHMe, where X=Gly, Ala, Aib and Cage. J. Mol. Struc. (Theochem) 731, 127–137.

    Article  CAS  Google Scholar 

  175. Huston, S. E., and Marshall, G. R. (1994) Alpha/3(10)-helix transitions in alpha-methylalanine homopeptides: Conformational transition pathway and potential of mean force. Biopolymers 34, 75–90.

    Article  PubMed  CAS  Google Scholar 

  176. Van Roey, P., Smith, G. D., Balasubramanian, T. M., Czerwinski, E. W., Marshall, G. R., and Mathews, F. S. (1983) Crystal and molecular structure of tert.-butyloxycarbonyl-L-prolyl-alpha-aminoisobutyryl-L-alanyl-alpha- aminoisobutyrate methyl ester. Int. J. Pept. Protein Res. 22, 404–409.

    Article  PubMed  Google Scholar 

  177. Prasad, B. V., and Balaram, P. (1984) The stereochemistry of peptides containing alpha-aminoisobutyric acid. CRC Crit. Rev. Biochem. 16, 307–348.

    Article  PubMed  CAS  Google Scholar 

  178. Karle, I. L., Flippen-Anderson, J. L., Uma, K., and Balaram, P. (1993) Unfolding of an alpha-helix in peptide crystals by solvation: Conformational fragility in a heptapeptide. Biopolymers 33, 827–837.

    Article  PubMed  CAS  Google Scholar 

  179. Toniolo, C., Crisma, M., Formaggio, F., Valle, G., Cavicchioni, G., Precigoux, G., Aubry, A., and Kamphuis, J. (1993) Structures of peptides from alpha-amino acids methylated at the alpha-carbon. Biopolymers 33, 1061–1072.

    Article  PubMed  CAS  Google Scholar 

  180. Andersen, N. H., Liu, Z., and Prickett, K. S. (1996) Efforts toward deriving the CD spectrum of a 3(10) helix in aqueous medium. FEBS Lett. 399, 47–52.

    Article  PubMed  CAS  Google Scholar 

  181. Monaco, V., Formaggio, F., Crisma, M., Toniolo, C., Hanson, P., Millhauser, G., George, C., Deschamps, J. R., and Flippen-Anderson, J. L. (1999) Determining the occurrence of a 3(10)-helix and an alpha-helix in two different segments of a lipopeptaibol antibiotic using TOAC, a nitroxide spin-labeled C(alpha)-tetrasubstituted alpha-aminoacid. Bioorg. Med. Chem. 7, 119–131.

    Article  PubMed  CAS  Google Scholar 

  182. Higashimoto, Y., Kodama, H., Jelokhani-Niaraki, M., Kato, F., and Kondo, M. (1999) Structure-function relationship of model Aib-containing peptides as ion transfer intermembrane templates. J. Biochem. (Tokyo) 125, 705–712.

    Article  CAS  Google Scholar 

  183. Karle, I. L. (2001) Controls exerted by the Aib residue: Helix formation and helix reversal. Biopolymers 60, 351–365.

    Article  PubMed  CAS  Google Scholar 

  184. Howl, J., Prochazka, Z., Wheatley, M., and Slaninova, J. (1999) Novel strategies for the design of receptor-selective vasopressin analogues: Aib-substitution and retro-inverso transformation. Br. J. Pharmacol. 128, 647–652.

    Article  PubMed  CAS  Google Scholar 

  185. Creamer, T. P., and Rose, G. D. (1992) Side-chain entropy opposes alpha-helix formation but rationalizes experimentally determined helix-forming propensities. Proc. Natl. Acad. Sci. U.S.A. 89, 5937–5941.

    Article  PubMed  CAS  Google Scholar 

  186. Maison, W., Arce, E., Renold, P., Kennedy, R. J., and Kemp, D. S. (2001) Optimal N-caps for N-terminal helical templates: Effects of changes in H-bonding efficiency and charge. J. Am. Chem. Soc. 123, 10245–10254.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  189. Davis, J. M., Truong, A., and Hamilton, A. D. (2005) Synthesis of a 2,3¢;6¢,3″-terpyridine scaffold as an alpha-helix mimetic. Org. Lett. 7, 5405–5408.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  191. Ernst, J. T., Becerril, J., Park, H. S., Yin, H., and Hamilton, A. D. (2003) Design and application of an alpha-helix-mimetic scaffold based on an oligoamide-foldamer strategy: Antagonism of the Bak BH3/Bcl-xL complex. Angew. Chem. Int. Ed. Engl. 42, 535–539.

    Article  PubMed  CAS  Google Scholar 

  192. Che, Y., Brooks, B. R., and Marshall, G. R. (2007) Protein recognition motifs: Design of peptidomimetics of helix surfaces. Biopolymers 86, 288–297.

    Article  PubMed  CAS  Google Scholar 

  193. Biros, S. M., Moisan, L., Mann, E., Carella, A., Zhai, D., Reed, J. C., and Rebek, J. Jr. (2007) Heterocyclic alpha-helix mimetics for targeting protein-protein interactions. Bioorg. Med. Chem. Lett. 17, 4641–4645.

    Article  PubMed  CAS  Google Scholar 

  194. Restorp, P., and Rebek, J. (2008) Synthesis of a-helix mimetics with four side-chains. Bioorg. Med. Chem. Lett. 18, 5905–5911.

    Article  CAS  Google Scholar 

  195. Ahn, J.-M., and Han, S.-Y. (2007) Facile synthesis of benzamides to mimic an a-helix. Tetrahedron Lett. 48, 3543–3547.

    Article  CAS  Google Scholar 

  196. Todd, M. J., Semo, N., and Freire, E. (1998) The structural stability of the HIV-1 protease. J. Mol. Biol. 283, 475–488.

    Article  PubMed  CAS  Google Scholar 

  197. Shultz, M. D., and Chmielewski, J. (1999) Probing the role of interfacial residues in a dimerization inhibitor of HIV-1 protease. Bioorg. Med. Chem. Lett. 9, 2431–2436.

    Article  PubMed  CAS  Google Scholar 

  198. Zutshi, R., Brickner, M., and Chmielewski, J. (1998) Inhibiting the assembly of protein-protein interfaces. Curr. Opin. Chem. Biol. 2, 62–66.

    Article  PubMed  CAS  Google Scholar 

  199. Bowman, M. J., and Chmielewski, J. (2002) Novel strategies for targeting the dimerization interface of HIV protease with cross-linked interfacial peptides. Biopolymers 66, 126–133.

    Article  PubMed  CAS  Google Scholar 

  200. Randolph, J. T., and DeGoey, D. A. (2004) Peptidomimetic inhibitors of HIV protease. Curr. Top. Med. Chem. 4, 1079–1095.

    Article  PubMed  CAS  Google Scholar 

  201. Chrusciel, R. A., and Strohbach, J. W. (2004) Non-peptidic HIV protease inhibitors. Curr. Top. Med. Chem. 4, 1097–1114.

    Article  PubMed  CAS  Google Scholar 

  202. Miller, M., Schneider, J., Sathyanarayana, B. K., Toth, M. V., Marshall, G. R., Clawson, L., Selk, L., Kent, S. B., and Wlodawer, A. (1989) Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. Science 246, 1149–1152.

    Article  PubMed  CAS  Google Scholar 

  203. Miller, M., Geller, M., Gribskov, M., and Kent, S. B. (1997) Analysis of the structure of chemically synthesized HIV-1 protease complexed with a hexapeptide inhibitor. Part I: Crystallographic refinement of 2 A data. Proteins 27, 184–194.

    Article  PubMed  CAS  Google Scholar 

  204. Smith, A. B. III, Hirschmann, R., Pasternak, A., Akaishi, R., Guzman, M. C., Jones, D. R., Keenan, T. P., Sprengeler, P. A., Darke, P. L., and Emini, E. A. (1994) Design and synthesis of peptidomimetic inhibitors of HIV-1 protease and renin. Evidence for improved transport. J. Med. Chem. 37, 215–218.

    Article  PubMed  CAS  Google Scholar 

  205. Smith, A. B. III, Nittoli, T., Sprengeler, P. A., Duan, J. J., Liu, R. Q., and Hirschmann, R. F. (2000) Design, synthesis, and evaluation of a pyrrolinone-based matrix metalloprotease inhibitor. Org. Lett. 2, 3809–3812.

    Article  PubMed  CAS  Google Scholar 

  206. Phillips, S. T., Blasdel, L. K., and Bartlett, P. A. (2005) @-tides as reporters for molecular associations. J. Am. Chem. Soc. 127, 4193–4198.

    Article  PubMed  CAS  Google Scholar 

  207. Phillips, S. T., Rezac, M., Abel, U., Kossenjans, M., and Bartlett, P. A. (2002) “@-Tides”: The 1,2-dihydro-3(6H)-pyridinone unit as a beta-strand mimic. J. Am. Chem. Soc. 124, 58–66.

    Article  PubMed  CAS  Google Scholar 

  208. Hammond, M. C., Harris, B. Z., Lim, W. A., and Bartlett, P. A. (2006) Beta strand peptidomimetics as potent PDZ domain ligands. Chem. Biol. 13, 1247–1251.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported in part by an NIH research grant (GM 68460) to GRM. YC also acknowledges the Lenfant Biomedical Fellowship from the National Heart, Lung and Blood Institute. DJK acknowledges financial support from the Ewing Marion Kauffman Foundation and the Computational Biology Training Grant at Washington University in St. Louis. The authors acknowledge continued support from the Department of Biochemistry and Molecular Biophysics and the Center for Computational Biology at Washington University Medical School.

Author information

Authors and Affiliations

  1. Departments of Biochemistry and Molecular Biophysics and Biomedical Engineering, Washington University, St. Louis, MO, USA

    Garland R. Marshall

  2. Biomedical Engineering, Washington University, St. Louis, MO, USA

    Daniel J. Kuster

  3. Exploratory Medicinal Sciences, Pfizer Global Research & Development, Groton, CT, USA

    Ye Che

Authors
  1. Garland R. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. Kuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ye Che
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Spiegelbergstr. 29, Basel, 4059, Switzerland

    Edgar Jacoby

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Marshall, G.R., Kuster, D.J., Che, Y. (2009). Chemogenomics with Protein Secondary-Structure Mimetics. In: Jacoby, E. (eds) Chemogenomics. Methods in Molecular Biology, vol 575. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-274-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-274-2_5

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-273-5

  • Online ISBN: 978-1-60761-274-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation