A novel peptide delivery system involving peptidase activated prodrugs as antimicrobial agents. Synthesis and biological activity of peptidyl derivatives of 5-fluorouracil

Abstract

As an approach to the development of antimicrobial agents, a novel peptide carrier system was designed, based on the chemical instability of .alpha.-substituted glycine analogs, with the explicit intent of actively transporting therapeutically useful compounds into microbial cells. Peptides containing 5-fluorouracil (5-FU) linked to the peptide backbone were selected to test the feasibility of this new delivery system. These peptide conjugates were designed such that they would be substrates for both the microbial peptide permeases and peptidases. After entry into cells, enzymatic hydrolysis of the peptide generated an unstable .alpha.-(5-FU)-glycine that spontaneously decomposed to release 5-FU. The 5-FU-peptide conjugates were tested for antifungal (Candida albicans) and antibacterial (Escherichia coli) activity, and had antimicrobial activities comparable to free 5-FU. Noninhibitory peptides antagonized the antimicrobial activities of the 5-FU-peptide conjugates but not of free 5-FU, a result consistent with peptide transport mediated entry of the peptide conjugates into cells. Further support for this conclusion was provided by the finding that biological activities were dependent upon peptide stereochemistry.