PEGylated prodrugs of antidiabetic peptides amylin and GLP-1.
J Control Release
; 292: 58-66, 2018 12 28.
Article
em En
| MEDLINE
| ID: mdl-29729352
ABSTRACT
Agonists of the glucagon-like peptide-1 (GLP-1) receptor and analogs of human amylin have been studied for almost two decades due to their therapeutic potential to treat diabetes mellitus and obesity. Both native peptides exhibit unfavorable pharmacokinetics. Even optimized analogs less prone to proteolysis have to be applied at least daily or once-weekly utilizing microsphere formulations or fusion to proteins. Thus, innovative approaches allowing tuning the drug levels to achieve beneficial therapeutic responses and prolonged application intervals are demanded. PEGylation, i.e., conjugation of polyethylene glycol (PEG), has enhanced the bioavailability of several drugs but does not appear to be useful for amylin and GLP-1. Thus, we developed a traceless prodrug strategy using protease-cleavable peptide linkers that can release therapeutic peptides. Specifically, the release kinetics of linker sequences LVPR, LDPR, and LVPRLVPR were tested in combination with GLP-1 analog taspoglutide, amylin, and amylin analog pramlintide in mouse serum. The linkers allowed tuning the taspoglutide release over more than one order of magnitude providing stable serum levels from ~0.08 to 3⯵mol/L for ~20â¯h. Amylin and pramlintide levels were ~20â¯nmol/L and stable for at least 24â¯h. Importantly, all peptide therapeutics were protected against proteolytic degradation within the prodrug, especially the N-terminal sequences near the PEG. Thus, taspoglutide was released even after an incubation period of 24â¯h in serum with the content of degraded taspoglutide being below 2% in the prodrug at this time point. This PEG-prodrug technology could provide precisely tuned long-acting anti-diabetic and anti-obesity therapies and even once-monthly administration intervals when combined with other formulation strategies.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Peptídeos
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Polietilenoglicóis
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Pró-Fármacos
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Hipoglicemiantes
Limite:
Animals
Idioma:
En
Revista:
J Control Release
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Alemanha