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Pharmaceutical Research

, Volume 13, Issue 11, pp 1657–1662 | Cite as

The Effect of Conformation on Membrane Permeability of an Acyloxyalkoxy-linked Cyclic Prodrug of a Model Hexapeptide

  • Sanjeev Gangwar
  • Seetharama D. S. Jois
  • Teruna J. Siahaan
  • David G. Vander Velde
  • Valentine J. Stella
  • Ronald T. Borchardt
Article

Abstract

Purpose. To determine the different conformations of the acyloxyalkoxy-linked cyclic prodrug 1 of the model hexapeptide 2 in solution and to investigate the relationship between these solution conformations and the cellular permeability characteristics of this prodrug.

Methods. Two-dimensional Homonuclear Hartmann-Hahn spectroscopy, Rotating-Frame Overhouser effect spectroscopy, circular dichroism and molecular dynamics simulations were used to find the solution conformers of cyclic prodrug 1.

Results. Our spectroscopic findings suggest that cyclic prodrug 1 exhibits a major and a minor conformer in solution. The major conformer appears to have a well-defined secondary structure, which involves a β-turn and 4 → 1 intramolecular hydrogen bond, creating a compact structure with a reduced average hydrodynamic radius compared to the model hexapeptide 2.

Conclusions. The increased ability of cyclic prodrug 1 to permeate membranes compared to the model hexapeptide 2 could be due to reduction in the average hydrodynamic radius of the molecule facilitating paracellular flux and/or the reduction in the hydrogen bonding potential facilitating transcellular flux.

esterase-sensitive prodrug peptide delivery membrane permeability solution conformation nuclear magnetic resonance spectroscopy circular dichroism 

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REFERENCES

  1. 1.
    S. S. Davis. In S. S. Davis, L. Illum, and E. Tomlinson (eds.), Delivery Systems for Peptide Drugs, Plenum Press, New York, 1986, pp. 1–21.Google Scholar
  2. 2.
    M. J. Humphrey. In S. S. Davis, L. Illum, and E. Tomlinson (eds.), Delivery Systems for Peptide Drugs, Plenum Press, New York, 1986, pp. 139–151.Google Scholar
  3. 3.
    W. T. Cefalu and W. M. Pardridge. J. Neurochem. 45:1954–1956 (1985).Google Scholar
  4. 4.
    H. D. Kleinert, S. H. Rosenberg, W. R. Baker, H. H. Stein, V. Klinghofer, J. Barlow, K. Spina, J. Polakowski, P. Kovar, J. Cohen, and J. Denissen. Science 257:1940–1943 (1992).Google Scholar
  5. 5.
    R. A. Conradi, A. R. Hilgers, N. F. H. Ho, and P. S. Burton. Pharm. Res. 9:435–439 (1992).Google Scholar
  6. 6.
    P. S. Burton, R. A. Conradi, A. R. Hilgers, N. F. H. Ho, and L. L. Maggiora. J. Control. Release 19:87–98 (1992).Google Scholar
  7. 7.
    G. M. Pauletti, S. Gangwar, F. W. Okumu, T. J. Siahaan, V. J. Stella, and R. T. Borchardt. Pharm. Res. 13:1613–1621 (1996).Google Scholar
  8. 8.
    F. W. Okumu, G. M. Pauletti, D. G. Vander Velde, T. J. Siahaan, and R. T. Borchardt. Pharm. Res. 12:S-302 (1995).Google Scholar
  9. 9.
    S. Gangwar, G. M. Pauletti, T. J. Siahaan, V. J. Stella, and R. T. Borchardt. J. Org. Chem. (submitted).Google Scholar
  10. 10.
    A. Bax and D. G. Davis. J. Magn. Reson. 63:207–213 (1985).Google Scholar
  11. 11.
    K. Wüthrich. NMR of Proteins and Nucleic Acids, Wiley, New York, 1986.Google Scholar
  12. 12.
    G. N. Ramachandran and A. K. Mitra. J. Mol. Biol. 107:85–92 (1976).Google Scholar
  13. 13.
    A. Perczel, K. Park, and G. D. Fasman. Anal. Biochem. 203:83–93 (1992).Google Scholar
  14. 14.
    A. Perczel and G. D. Fasman. Protein Science 1:378–395 (1992).Google Scholar
  15. 15.
    M. Kock, H. Kessler, D. Seebach, and A. Thaler. J. Am. Chem. Soc. 114:2676–2686 (1996).Google Scholar
  16. 16.
    V. F. Bystrov. Prog. NMR Spectros. 10;41–81 (1976).Google Scholar
  17. 17.
    G. D. Rose, L. M. Gierasch, and J. A. Smith. Adv. Protein Chem. 37:1–109 (1985).Google Scholar
  18. 18.
    G. M. Pauletti, S. Gangwar, G. T. Knipp, M. M. Nerurkar, F. W. Okumu, K. Tamura, T. J. Siahaan, and R. T. Borchardt. J. Control. Release 41:3–17 (1996).Google Scholar
  19. 19.
    G. T. Knipp, N. F. H. Ho, C. L. Barsuhn, and R. T. Borchardt. Pharm. Res. 12:S-302 (1995).Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Sanjeev Gangwar
    • 1
  • Seetharama D. S. Jois
    • 1
  • Teruna J. Siahaan
    • 1
  • David G. Vander Velde
    • 1
  • Valentine J. Stella
    • 1
  • Ronald T. Borchardt
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence

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