PEGylated Oligothioetheramide Prodrugs Activated by Host Serum Proteases.
Chembiochem
; 22(17): 2697-2702, 2021 09 02.
Article
in En
| MEDLINE
| ID: mdl-34227209
ABSTRACT
Due to the increasing prominence of antibiotic resistance, novel drug discovery and delivery approaches targeting bacteria are essential. In this work we evaluate a prodrug design to improve the cytotoxic profile of polycationic oligothioetheramides (oligoTEAs), which are promising antimicrobials. Herein we chemically modify the oligoTEA, PDT-4G, with a polyethylene glycol (PEG) and show that 1, 2, and 5â
kDa PEGs mitigate cytotoxicity. As PEGylation reduces antibacterial activity, we evaluate two peptide linkers which, unlike oligoTEAs, are susceptible to proteolytic cleavage in serum. To gain insight into the prodrug reactivation, two linkers were tested, the 5-residue peptide sequence LMPTG, and the dipeptide sequence VC-PABC. In the presence of 20 % serum, prodrugs made with the VC-PABC linker successfully inhibited bacterial growth. Overall, we observed reactivation of oligoTEAs facilitated by serum protease cleavage of the peptide linkers. This work opens the door to the future design of antimicrobial prodrugs with tunable release profiles.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prodrugs
Language:
En
Journal:
Chembiochem
Journal subject:
BIOQUIMICA
Year:
2021
Document type:
Article
Affiliation country:
United States