Functional Group Approaches to Prodrugs: Functional Groups in Peptides
There is no doubt that peptides play critical roles in various biological processes. Naturally, a large number of biologically active peptides have been discovered, many of which are clinically used pharmaceutical agents. However, there are intrinsic physicochemical and pharmaceutical properties associated with peptides that hinder their development as oral- and CNS-active pharmaceutical agents. These properties include high polarity and hydrogen-bonding potential, and the presence of charged functional groups, all of which are significant contributing factors to the generally poor permeation properties of peptides across membrane barriers. In addition, peptides typically undergo rapid metabolism, which leads to short half-lives in vivo (<30 min). Consequently, peptides are generally considered poor candidates for development as orally and CNS-active pharmaceutical agents. Although the fundamental stability issues can sometimes be addressed with structural modifications and the introduction of Damino acids, the poor membrane permeation is generally intrinsic to the peptide structural features. One way to overcome this problem is the prodrug approach, i.e., to temporarily and bioreversibly mask those functional groups responsible for the undesirable physicochemical and pharmaceutical properties of peptides (Audus et al., 1995; Borchardt, 1995; Artursson and Borchardt, 1997; Gangwar et al., 1997b; Pauletti et al., 1997a; Shan et al., 1997; Wang et al., 1999c).
KeywordsOpioid Peptide Parent Peptide Phenylpropionic Acid Prodrug Approach Intramolecular Hydrogen Bond Formation
Unable to display preview. Download preview PDF.
- Audus K, Ng L, Wang W, and Borchardt RT. Brain Microvessel Endothelial Cell Culture Systems. In: Borchardt RT, Wilson G, and Smith P. Model Systems Used for Biopharmaceutical Assessment of Drug Absorption and Metabolism. New York, Plenum Press; 1996:239–258Google Scholar
- Borchardt RT, and Wang W. Prodrug Strategies to Improve the Oral Absorption of Peptides and Peptide Mimetics. In: Park K, and Mrsny RJ. Drug Delivery in the 21st Century. Washington, DC, American Chemical Society; 2000:36–45Google Scholar
- Bundgaard H, and Rasmussen GJ. Prodrugs of Peptides. 11. Chemical and Enzymatic Hydrolysis Kinetics of N-Acyloxymethyl Derivatives of a Peptide-like Bond. Pharm Res 1991b; 81238–1242Google Scholar
- Fentem JH, and Fry JR. Species Difference in the Metabolism and Hepatotoxicity of Coumarin. Comp Biochem Physiol 1993; 104C:1–8Google Scholar
- Ho NF, Raub TR, Burton PS, Barsuhn CL, Adson A, Audus KL, and Borchardt RT. Transport Processes in Pharmaceutical Systems. In: Amidon GL, Lee PI, and Topp EM. Quantitative Approaches to Delineate Transport Mechanisms in Cell Culture Monolayers. New York, Marcel Dekker; 1999:219–316Google Scholar
- National Toxicology Program Toxicology and Carcinogenesis. Studies of Coumarin; U.S. Department of Health and Human Services: Public Health Service and National Institutes of Health, 1993.Google Scholar
- Oliyai R, Safadi M, Meier PG, Hu M-K, Rich DH, and V.J. S. Kinetics of Acid Catalyzed Degradation of Cyclosporin A and its Analogs in Aqueous Solution. Int J Peptide Protein Res 1994; 43:239–247Google Scholar
- Pelkonen O, Raunio H, Rautio A, Pasanen M, and Lang MA. The Metabolism of Coumarin. In: O’Kennedy R, and Thornes RD, Coumarins Biology, Applications and Mode of Action. New York, John Wiley & Sons; 1997:67–92Google Scholar
- Wang B, Nimkar K, Wang W, Zhang H, Shan D, Gudmundsson O, Gangwar S, Siahaan T, and Borchardt RT. Synthesis and Evaluation of the Physicochemical Properties of Esterase-Sensitive Cyclic Prodrugs of Opioid Peptides Using Coumarinic Acid and Phenylpropionic Acid Linkers. J Peptide Res 1999a;53:370–382CrossRefGoogle Scholar
- Wang W, Jiang J, Ballard CE, and Wang B. Prodrug Approaches to the Improved Delivery of Peptide Drugs. Current Pharm Design 1999c; 5:265–287Google Scholar