Abstract
The clinical development of orally active peptide drugs has been limited by their unfavorable physicochemical characteristics (e.g., charge, hydrogen bonding potential, size), which prevent them from permeating biological barriers such as the intestinal mucosa, and also their lack of stability against enzymatic degradation (1–12). Unfortunately, many of the structural features of peptides (i.e., the N-terminal amino group and C-terminal carboxyl group, and side chain carboxyl, amino, and hydroxyl groups) that bestow upon the molecule affinity and specificity for its pharmacological receptor severely restrict its ability to permeate biological barriers and make the molecules substrates for peptidases. Therefore, successful oral delivery of peptides depends on strategies designed to alter the physicochemical characteristics of these potential drugs without changing their biological activity in order to circumvent the intestinal epithelial cells.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Amidon, G. L. and Lee, H. J. (1994) Absorption of peptide and peptidomimetic drugs. Annu. Rev. Pharmacol. Toxicol. 34, 321–341.
Burton, P. S., Conradi, R. A., Hilgers, A. R., Ho, N. F. H., and Maggiora, L. L. (1992) The relationship between peptide structure and transport across epithelial cell monolayers. J. Controlled Release 19, 87–98.
Burton, P. S., Conradi, R. A., and Ho, N. F. H. (1993) Evidence for a polarized efflux system for peptides in the apical region of Caco-2 cells. Biochem. Biophys. Res. Commun. 190, 760–766.
Bocci, V. (1990) Catabolism of therapeutic proteins and peptides with implications for drug delivery. Adv. Drug Delivery Rev. 4, 149–169.
Burton, P. S., Hill, R. B., and Conradi, R. A. (1987) Metabolism and transport of peptides across the intestinal mucosa. Proc. Int. Symp. Control. Rel. Bioact. Mater. 14, 6–7.
Conradi, R. A., Hilgers, A. R., Ho, N. F. H., and Burton, P. S. (1992) The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 435–439.
Conradi, R. A., Wilkinson, K. F., Rush, B. D., Hilgers, A. R., Ruwart, M. J., and Burton, P. S. (1993) In vitro/in vivo models for peptide oral absorption: comparison of Caco-2 cell permeability with rat intestinal absorption of renin inhibitory peptides. Pharm. Res. 10, 1790–1792.
Lee, V. H. L. (1988) Enzymatic barriers to peptide and protein absorption. Crit. Rev. Ther. Drug Carrier Syst. 5, 69–97.
Lee, V. H. L. and Yamamoto, A. (1990) Penetration and enzymatic barriers to peptide and protein absorption. Adv. Drug Delivery Rev. 4, 171–207.
Lee, V. H. L., Dodda-Kashi, S., Grass, G. M., and Rubas, W. (1991) Oral route of peptide and protein delivery, in Peptide and Protein Drug Delivery (Lee, V. H. L., ed.), Marcel Dekker, New York, pp. 691–738.
Lee, V. H. L., Traver, R. D., and Taub, M. E. (1991) Enzymatic barriers to peptide and protein drug delivery, in Peptide and Protein Drug Delivery (Lee, V. H. L., ed.), Marcel Dekker, New York, pp. 303–357.
Zhou, X. H. (1994) Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs. J. Controlled Release 29, 239–252.
Gray, R. A., Vander Velde, D. G., Burke, C. J., Manning, M. C, Middaugh, C. R., and Borchardt, R. T. (1994) Delta-sleep-inducing peptide: solution conformation studies of a membrane-permeable peptide. Biochemistry 33, 1323–1331.
Alexander, J., Fromtling, R. A., Bland, J. A., Pelak, B. A., and Gilfillan, E. C. (1991) (Acyloxy)alkyl carbamate prodrugs of norfloxacin. J. Med. Chem. 34, 78–81.
Folkmann, M. and Lund, F. J. (1990) Acyloxymethyl carbonochloridates. New intermediates in prodrug synthesis. Synthesis 1159–1166.
Gangwar, S., Pauletti, G. M., Siahaan, T. J., Stella, V. J., and Borchardt, R. T. (1996) Synthesis of a novel prodrug of a hexapeptide using acyloxyalkoxy promoiety which has increased stability to peptidase metabolism and increased cellular permeability. J. Org. Chem. 62, 1356–1362.
Gogate, U. S., Repta, A. J., and Alexander, J. (1987) N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. I. Kinetics and mechanism of degradation in aqueous solutions. Int. J. Pharm. 40, 235–248.
Gogate, U. S. and Repta, A. J. (1987) N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. Esterase-catalyzed release of parent amines from model prodrugs. J. Pharm. Sci. 40, 249–255.
Atherton, E. and Sheppard, R. C. (1989) Solid Phase Peptide Synthesis: A Practical Approach, 2nd ed., IRL, Oxford.
Greene, T. W. and Wuts, P. G. M. (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley, New York, pp. 240–241.
Diago-Meseguer, J., Palomo-Coll, A. L., Fernandez-Lizarbe, J. R., and Zugaza-Bilbabo, A. (1980) A new reagent for activating carboxyl groups: Preparation and reaction of N,N-Bis(2-oxo-3-oxazolidinyl)-phosphinic chloride. Synthesis 547–551.
Pauletti, G. M, Gangwar, S., Okumu, F. W., Siahaan, T. J., Stella, V. J., and Borchardt, R. T. (1996) Esterase-sensitive cyclic prodrugs of peptides: Evaluation of the acyloxyalkoxy promoiety in a model hexapeptide. Pharm. Res. 13, 1615–1623.
Hidalgo, I. J., Raub, T. J., and Borchardt, R. T. (1989) Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96, 736–749.
Wilson, G., Hassan, I. F., Dix, C. J., Williamson, I., Shah, R., and Mackay, M. (1990) Transport and permeability properties of human Caco-2 cells: An in vitro model of the intestinal epithelial cell barrier. J. Controlled Release 11, 25–40.
Pinto, M., Robine-Leon, S., Appay, M.D., Kedinger, M., Tradou, N., Dussaulx, E., Lacroix, B., Simon-Assmann, P., Haffen, K., Fogh, J., and Zweibaum, A. (1983) Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture. Biol. Cell 47, 323–330.
Artursson, P. (1990) Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J. Pharm. Sci. 79, 476–482.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Humana Press Inc., Totowa, NJ
About this protocol
Cite this protocol
Gangwar, S., Pauletti, G.M., Siahaan, T.J., Stella, V.J., Borchardt, R.T. (1999). Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model Hexapeptide Having Enhanced Membrane Permeability and Enzymatic Stability Using an Acyloxyalkoxy Promoiety. In: Kazmierski, W.M. (eds) Peptidomimetics Protocols. Methods in Molecular Medicine™, vol 23. Humana Press. https://doi.org/10.1385/0-89603-517-4:37
Download citation
DOI: https://doi.org/10.1385/0-89603-517-4:37
Publisher Name: Humana Press
Print ISBN: 978-0-89603-517-1
Online ISBN: 978-1-59259-605-8
eBook Packages: Springer Protocols