Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid.

ABSTRACT: Noncovalent binding of peptides to human serum albumin protects against renal clearance and enzymatic degradation. Herein, we investigated the effect of mycophenolic acid (MPA) albumin binders for improving the stability of peptides. For proof-of-principle, the short acting glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide was selected and functionalized with different MPA albumin binders. In vitro, all lixisenatide analogues showed well preserved GLP-1 receptor activation potency. High performance affinity chromatography (HPAC) and ultrafiltration analyses indicated that DiMPA was able to confer high albumin affinity to lixisenatide and revealed that affinity is increased for DiMPA modified lixisenatide analogues containing OEG spacers. In db/db mice, the selecte

SUBMITTER: Tang C 

PROVIDER: S-EPMC9050719 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature