The utility of the prodrug approach to improve peptide absorption

Abstract

A major obstacle to the application of peptides as clinically useful drugs is their poor biomembrane penetration, rapid enzymatic degradation and short biological half-lives. A possible approach to solve these delivery problems of peptide drugs is derivatization of the peptides to produce prodrugs or transport forms which are more lipophilic than the parent peptides and capable of protecting these against degradation by enzymes present at the mucosal barrier or in the blood. The potential utility of this prodrug approach to protect peptides against degradation by various proteolytic enzymes is illustrated with a number of examples including prodrugs of the peptide bond itself, the C-terminal amide group in peptide amides, the tyrosine phenol group in tyrosyl peptides and the N-terminal amino group. Lipophilic prodrugs of the tripeptide TRH have been found useful to achieve transdermal delivery of the peptide. It is concluded that the prodrug technology may offer a promising means to overcome the enzymatic and penetration barriers in the delivery of several peptide drugs.