Using Disease-Associated Enzymes to Activate Antimicrobial Peptide Prodrugs

Abstract

Prodrugs of antimicrobial peptides can be generated by modifying their sequences at their N-termini with a linker and a negatively charged promoiety. These modifications can be selectively reversed by a disease-associated enzyme, thereby confining the activity of the peptide to pathologically affected body parts. A general method for the generation of prodrug candidates, based on a linker constituting the substrate of a disease-associated protease and an oligo-glutamic acid promoiety, as well as a protocol to validate the activation of the prodrug, are described herein.

Emerging Nanomedicine Therapies to Counter the Rise of Methicillin-Resistant Staphylococcus aureus

“…To address this, AMPs are now being developed with modified peptide sequences to enhance activity [ 84 , 91 , 92 ] or are being synthesized as pro-drugs or “peptidomimetics” to avoid toxicity issues, enhance retention, and allow for improved efficacy at the site of action. Several strategies exist to achieve this, including modifying the carbon chain length and functional group [ 90 ], PEGylation, net charge reduction [ 93 ], nanoparticle or antibody conjugation [ 94 , 95 ], and synergistic delivery with or antibiotics [ 96 ].…”

PEGylated Oligothioetheramide Prodrugs Activated by Host Serum Proteases

“…[24,26,27] Several recent studies have also used this approach to improve the therapeutic potential of AMPs. These prodrugs incorporate promoieties designed to mask cationic charge and/or reduce hydrophobicity including: negatively-charged oligoglutamic acid, [23,[28][29][30][31][32][33] mPEG-phenylglyoxal reagents, [34] or polyethylene glycol. [35] Polyethylene glycol (PEG) has been used in several antibacterial agents and prodrugs to impart favorable properties including longer half-life in vivo, reduced immunogenicity, lower toxicity, increased solubility, and improved stability.…”