Functional Group Approaches to Prodrugs: Functional Groups in Peptides

Abstract

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).